Through a chance meeting in a hospital in New York, Sam Morgan mistook Dr. Silas Clay for his recently deceased brother, Stephen Clay. Stephen had kidnapped and terrorized Sam. When Sam learned that Silas and Stephen were brothers, she introduced herself and informed Silas of Stephen's mental instability and the crimes that Stephen had committed before his death. Silas admitted that he had been out of touch with his brother for several years but did not show much emotion upon learning of his brother's death or the news that Stephen had a son named Rafe.

After processing the news of Stephen's life and death, Silas arrived in Port Charles and petitioned the court to gain custody of his nephew, although Sam was glad to be Rafe's foster parent. Rafe had witnessed the death of his mother at Stephen's hands, and Sam warned Silas that Rafe would be unsettled by the resemblance between brothers. Rafe reacted as Sam had predicted. Regardless, Silas moved forward with his plan to raise Rafe.

The court ruled in favor of Silas, and he was granted legal guardianship of Rafe. At the same time, Silas met Sam's son Danny and diagnosed the young child with leukemia. Silas believed that Sam would need to focus on her child and thought her life would be easier without Rafe. However, Silas changed his mind and allowed Rafe to remain with Sam while Danny battled his illness. Silas took a professional interest in Danny's case and felt that General Hospital was providing inferior care to cancer patients. He voiced his concerns to the Chief of Staff and took a position as the Head of Oncology at General Hospital.

Shortly after Silas began his new position, he ran into a woman from his past named Ava Jerome. He was shocked to learn that Ava had a daughter and wondered if he could be the girl's father. Ava insisted that her daughter was conceived long after she and Silas had ended their relationship and claimed that another patient in the hospital, Robert "Franco" Frank, was her child's father. However, Ava's lie was revealed when the newspaper ran an article on Kiki's paternity, which confirmed that Silas was listed as the father on Kiki's birth certificate.

Silas acknowledged that Kiki's life was torn apart by Ava's lies and decided to give Kiki a bit of space instead of forcing his way in to his daughter's life. Meanwhile, he improved his relationships with both Sam and Rafe by saving Danny's life. Silas and Sam shared a kiss while Ava made an attempt to rekindle what they had once shared. Silas refused Ava's advances and hoped to see Sam for romantic reasons after her son was released from the hospital.

Sam agreed to see Silas romantically, and they began to date as Rafe willingly moved in with Silas. As Silas' relationship with Sam became more serious, Nathan West, a New York police officer, contacted him. Ava was contacted as well, and Silas feared that Sam would leave him if she learned the secret that Silas and Ava shared. After Silas and Sam became lovers, Nathan joined the Port Charles Police Department. Nathan informed Sam that she was involved with a married man. Silas was forced to reveal that he was married but explained that his wife, Nina, had been in a coma for more than twenty years. Silas told Sam that Nina had overdosed on pills when she had learned about his affair with Ava. Silas blamed himself for what had happened, as did his wife's family.

Even though Silas was a suspect in his wife's attempted murder, he swore his innocence to Sam, and he was relieved that she believed him. Sam offered to use her private investigator skills to clear Silas of any wrongdoing by finding the person that had harmed his wife. Sam and Silas agreed that Ava was a likely suspect, while Nathan remained convinced that Silas had committed the crime.

Together Silas and Sam forced their way into the clinic where Nina resided, but Silas was unable to find his wife. The room assigned to her was empty, and he feared that she had passed away. A few weeks later, Nina's mother, Madeline Reeves, arrived in Port Charles and confirmed that Nina was dead. Together Sam, Silas, and Nathan set a trap for the person that had harmed Nina, and they were shocked to learn that Madeline was at fault. She confessed that her intent had been to harm the baby Nina was carrying.

In the midst of Madeline's confessions, Nathan was revealed to be the man that had been raised by Madeline as Nina's brother. Silas and Nathan made peace with one another as they each grieved for Nina, and Silas mourned the loss of the child he had never known. As Silas accepted his wife's death, he professed his love to Sam but discovered that Nina was alive immediately after. His wife was wheelchair-bound while she developed her strength after over two decades in a coma. Nina remained in love with Silas and planned to resume their marriage. Instead, Silas admitted that he had moved on with Sam but would support Nina through her recovery as her friend. He offered her a place to stay.

Nina's return placed an enormous strain on Silas' relationship with Sam. He refused to believe Sam's accusations that Nina wanted to destroy what they had, and their romance ended. Silas temporarily tried to reconnect with Nina but was uncomfortable with her plans for the future, which included a child. Eventually, Silas realized that Sam's theory about Nina had been correct, and he learned that Nina had manipulated him for months. He apologized to Sam, but by that time, she was dating someone else.

After Silas learned the truth about Nina, he focused on his relationship with Kiki. Per his daughter's request, he provided medical care for Kiki's mother, Ava, while she was in danger from her unborn child's father, Sonny Corinthos. Nina also posed a threat to Ava and her baby, and she forced Ava into labor and kidnapped the newborn. Silas helped Ava search for her infant daughter even after he learned that Ava was wanted by the police for the murder of Connie Falconeri. After Ava's daughter was rescued, Silas helped Kiki care for the baby while Ava was incarcerated.

Ava had enemies inside of prison, and she feared for her life. Silas promised to help Ava in any way that he could, and she took him up on his offer after she escaped from prison. Ava was injured from a gunshot wound and a fall, and the police assumed that she had died. Silas hid Ava at a hospital in New York and tended to her injuries. He did not tell the police that Ava was alive but instead informed Ava that she had cancer. He urged Ava to fight the disease and refused to kill her as she had requested.

Silas allowed Ava to believe that he would euthanize her but instead, he kidnapped Ava's daughter Avery and used her bone marrow to save Ava's life. When Ava recovered, she was furious with Silas instead of grateful. She sneaked away from the hospital and emerged in Port Charles under the name Denise DeMuccio, Ava's twin sister. Silas doubted that Ava's identity would remain secret, and he urged her to leave town. He was forced to go along with her plan after Ava threatened to reveal that he had kidnapped Avery. Later Silas warned Morgan to keep his hands off Denise and said he knew about Morgan and Denise's illicit encounters. Morgan assured Silas that he had no idea what Silas was talking about. After Silas told Morgan that Denise had admitted that they had been together, Morgan begged Silas not to tell Kiki, and Silas agreed reluctantly.

Nina visited Silas and told him she'd been hearing a baby crying, and she was worried she was losing her sanity. Silas assured Nina that it would have been impossible for her to kidnap a baby and return it to Silas' apartment without being aware of what she'd done. Feeling guilty about Nina's suffering, Silas went to see Scott Baldwin but found Franco in Scott's office. Silas admitted to Franco that he'd been the one who had taken Avery, and he was going to turn himself in. In turn, Franco blurted out that Ava and Morgan were sleeping together behind Kiki's back.

Silas arrived at Ava's apartment and found Denise and Morgan in bed. When Morgan tried to explain, Silas cut him off and called Morgan a selfish, shallow, horny little brat who deserved to be screwed over the same way Morgan had betrayed Kiki. He said Morgan shouldn't have rekindled things with Kiki.

Alone with Ava, Silas thought Kiki deserved to know the truth about her faithless boyfriend and her sociopathic mother. Silas realized how little Morgan and Ava cared about Kiki. Silas told Ava he was going to confess to kidnapping Avery. Ava pointed out that the truth would destroy Kiki, but Silas remained confident that Kiki would get over it because Kiki was entitled to the truth, and he was going to make sure that Kiki knew everything when she returned from her trip.

After Franco told Nina that Silas had kidnapped Avery, Nina felt betrayed that Silas had once again chosen Ava over her. Nina decided to confront Silas.

Later, Franco went to Silas' apartment and stopped short when he saw the door was slightly ajar. Franco pushed the door open slowly and saw Nina kneeling next to Silas' body, clutching a large bloody knife.

It was later revealed that Madeline Reeves had stabbed Silas because he wouldn't sign over Nina's fortune to her.