Stefan came to Port Charles in 1996, bringing his nephew, Nikolas with him. Nikolas was Laura's son by his brother, Stavros Cassadine, and his bone marrow was needed to save his half-sister, Lulu. Stefan used this to pull Laura closer to him, as he had been in love with Laura ever since she was the captive bride of his brother. Stefan confessed his love to Laura, but she told him her heart belonged, as it always had, to Luke Spencer.

Stefan bailed General Hospital out of financial troubles, after he masterminded its downfall as an excuse to stay in Port Charles. Laura discovered that her mother, Lesley, who was believed to have died years ago in a car accident, was actually alive. Stefan had been holding her captive for several years. When Laura went into the building where Lesley was, it exploded. Stefan thought that he had lost Laura for good, but Luke and Laura had rigged the explosion to make it appear that she and Lesley were dead. That way they could hide out until they could figure out what Stefan was up to. Luke confronted Stefan with a gun, then left the gun on Spoon Island. Afterwards, when he heard noises, Stefan picked up the gun and fired, shooting Katherine Bell.

While obsessing over the paralyzed Katherine, Stefan married Bobbie Spencer Jones. He later divorced Bobbie when he discovered that she was working with her brother, Luke, to plot against him. Katherine and Stefan developed a relationship; this relationship concerned Stefan's cousin, Alexis. Alexis made it look like Katherine was the daughter of Stefan's father and his mistress, Kristin Bergman, because she thought Katherine was only marrying Stefan to manipulate him. Unfortunately, Stefan discovered the truth and banished Alexis from the Cassadine family. It was later discovered that Alexis was actually Stefan's sister.

Stefan and Katherine became engaged, but on the night of their engagement party, Katherine stepped into a trap set by Alexis and Luke, which was meant for Helena, and fell to her "death." Stefan was put on trial for Katherine's death and Alexis defended him because she felt responsible. During the trial, it was revealed that Nikolas was not Stefan's nephew, but rather his son. Once Alexis realized that Nikolas was not the prince and that Stefan had been lying to her all along, she decided to go after her share of the Cassadine fortune. Stefan was found not guilty because as it turned out, Katherine was not dead after all.

Stefan and Laura courted for a while, during which time, evidence was produced that confirmed Helena had paid off the doctor who delivered Nikolas and that Nikolas was actually Stavros' son, not Stefan's. Stefan's relationship with Laura seemed to always be rocky, but met its end when Stefan learned that his mother, Helena, was holding Laura's son, Lucky, captive having made it look as though he had died in a fire. Stefan attempted to save Lucky, but Helena snatched him back after the rescue. When Stefan told Laura what had happened, he learned that Luke had beaten him to the punch and Laura already knew. Laura refused to believe that he hand nothing to do with the kidnapping and said that even if he was innocent, he should have told her immediately that her son was alive rather than trying to use his heroic actions to gain her praise. The two broke up and Stefan continued trying to save Lucky from Helena. He wasn't successful though, because after sufficiently brainwashing him, Helena let Lucky go. He was eventually cured when he discovered what had happened.

When Stefan found out that designer Chloe Morgan was having psychic nightmares as a result of a brain tumor and seeing through the eyes of Helena, he knew immediately that he had to use this to his advantage. His opportunity came when he learned from his mother's servant, Andreas, that Helena was planning to kill him by giving him poisoned port. After learning what the poison was, he had an antidote developed so that when he drank the port, it would not hurt him. The plan went off without a hitch, and Stefan had everyone in Port Charles believing he was dead, including Helena and Nikolas. He then tracked down Chloe Morgan in Rome and had her kidnapped. She woke up on the Cassadine island in Greece, where Stefan convinced her that Helena had kidnapped both of them. For months they were "stranded" on the island while Stefan tried to predict Helena's next move through Chloe's dreams. He also started to fall for her, as there was an obvious attraction between them. His plan was brought to a halt though, when Chloe began to have trouble seeing. Without her radiation therapy for her tumor, she was at risk of going blind. Stefan realized that Chloe's health was more important than outsmarting his mother, and they made a successful "escape" back to Port Charles.

Once back home, Chloe discovered that Stefan had actually been her kidnapper, and despite his protests, she wanted nothing more to do with him. Upon discovery of Stefan's faked death, Nikolas also shut out Stefan. He was furious about being lied to, and instead of having Stefan take over as trustee of the Cassadine holdings, Nikolas gave Alexis the job. Stefan continues to find a way to get to Helena, while at the same time, gaining Nikolas' trust again.

As Stefan continued to be shunned by all around him, Helena began reviving Stavros, thought dead but secretly put into suspended animation for decades. As Stavros had always tormented Stefan for his weakness when they were children, Stavros couldn't resist anonymously manipulating Stefan (and Laura) once he returned to the world of the living. Stavros befriended Chloe, who was slowly thawing towards Stefan. Finally, she forgave him, and they planned to begin a relationship. Unfortunately, Chloe's psychic visions made her realize her new friend was Stefan's evil brother, and Stavros had to murder her. Stefan stumbled on her body, and found himself once again arrested for the murder of a woman he loved. Eventually, with the help of Luke of all people, Stefan escaped from jail, then cleared his name when Stavros' treachery was revealed. Stavros was killed during a fight with Luke. Helena was imprisoned, and Stefan finally found a semblance of joy as his family forgave him and he met his newfound half-sister, Kristina.

In January 2002, Stefan summoned his family to Wyndemere. Giving Kristina and Alexis valuable heirlooms from Russian ancestors they reminded him of, and Nikolas and Gia the keys to Wyndemere, Stefan announced that a childhood dream had been to leave the Cassadine legacy behind. He'd given up on that, until Chloe encouraged him to do what he wanted to do instead of what was expected of him. He decided to travel, starting with renting a villa in Milan. His family tearfully wished him farewell, knowing that arguably the most tortured member of the Cassadine dynasty had finally found happiness and peace of mind.

Apparently Stefan did not find the happiness he had sought, for he returned to a very different Port Charles in June, 2003. Laura was institutionalized. The Cassadine family was in shambles (Kristina dead, Alexis unstable, Nikolas heading up the family all on his own) and their coffers were severely depleted. Stefan came up with a plan for Nik to marry Lydia, the daughter of a Greek shipping magnate, in exchange for a large sum of cash. Nikolas refused and was far more interested in his friend Emily Quartermaine, whom he was slowly falling in love with. Not only was she ruining his plans, she refused to listen to his requests for her to leave Nikolas alone. Stefan paid a hit man to push Emily off the cliffs during an engagement party thrown in her and Nik's honor. The man pushed Lucky Spencer's girlfriend, Summer, instead. Stefan kept quiet as Luke was blamed for the crime and fled town. Soon after, he managed to coerce Nik into marrying Lydia, and Nik told him that he would never forgive or respect him again for his behavior. Nikolas also believed he was behind Summer's murder, but kept quiet in order to investigate. Meanwhile, in exchange for her legal services, Stefan began trying to help Alexis get custody of her daughter.

Stefan seemed to be in control up until a murderous Luke returned to Port Charles. Luke plotted revenge against Stefan. First, Luke kidnapped Stefan and tied him up in a warehouse. Next, Luke gathered up all of the people Stefan had hurt consisting of Nik, Lydia, Emily, Zander, and Alexis. Luke went on live television and he hosted his own trial. Everyone in Port Charles could witness the trial on TV and most of them did. Luke planned to get justice for Summer and Darius, but Stefan believed that Luke was just wasting his time. Towards the end of the trial, Stefan got really emotional. Stefan claimed that Nik was his only light in his otherwise miserable life and he blamed Helena for all of their troubles. Stefan revealed that Helena selfishly spent the Cassadine fortune that took generations to build. Stefan also admitted to killing Summer on Live TV, but Luke was one the Police Department arrested.

Stefan's final days were nothing but brutal. Luke broke into the Wyndemere Castle and planned to burn the place down. A fire did break out and Stefan got terribly burned. Stefan was taken to General Hospital. There, Alcazar told Stefan that he would let him live if he didn't tell anyone about Andy Capelli working for him. After being released from the hospital, Stefan kidnapped Lydia. Stefan tied Lydia up and he told her that they should have a baby together and pass it off as Nik's. Lydia refused, and Lucky arrived to rescue her. However, Stefan knocked him out. Stefan tied an unconscious Lucky up and left him in the study of the Wyndemere Castle. Luke's arrival led Stefan into holding Lydia hostage. Despite this, Lydia managed to escape Stefan's grasp, and she ran off. Luke and Stefan got into a fight with a knife, which resulted in Stefan getting stabbed. Stefan stumbled, but managed to whispered eerie words to Luke before he fell from the same cliff that Summer did.