Spencer Truman, a brilliant doctor, came to Llanview in 2005 with a secret agenda. His younger brother, David Vickers, and ex-wife, Dr. Paige Miller, were furious to have him back in their lives. Spencer had obviously wronged them in the past, and they were determined to usher him out of town. Spencer, however, made clear that he wasn't going anywhere.

When Spencer arrived, David was planning to marry Dorian. David revealed to Dorian that Spencer was his older brother and that David had changed his name years earlier to get as far away from the Trumans as he could. But David didn't tell Dorian that Spencer was blackmailing him with a secret from his past -- that David had killed a man. Spencer blackmailed David into jilting Dorian at the altar.

Spencer and Blair struck up a close friendship after he performed an emergency tracheotomy on her son, Jack. Little did Blair know that Spencer was in cahoots with Margaret Cochran, who had been obsessed with Todd and wound up pregnant with his baby after forcing Todd to have sex with her while holding him captive. Todd planned to kill Margaret after she nearly killed his daughter Starr, and lured her out of hiding with a personal ad. But Spencer warned Margaret that it could be a trap and gave her a plan to thwart Todd by pretending that she couldn't swim. Todd rowed her out onto a lake and prepared to drown her. When a woman matching Margaret's description was found washed up on shore, Todd was arrested for her murder, found guilty and sentenced to death. In reality, Margaret had thrown herself overboard and swam to safety. With Spencer's help, she faked her own death and lived in a warehouse until it was time to deliver her son. As Todd was being sentenced to death, Margaret went into labor and Spencer blackmailed Paige to help him deliver the baby. Spencer put the baby up for adoption, and the infant wound up in the home of childless couple Marcie and Michael McBain.

During this ordeal, Spencer wormed his way into Blair's life and helped convince her that Todd was guilty. Blair and Todd broke up, and she and Spencer became lovers.

Meanwhile, in an attempt to get some leverage over his brother, David started investigating Spencer's connection to Margaret. He pumped Paige for information and eventually realized that he was connected to Margaret's death. Spencer in turn revealed to David that the man he had supposedly killed when he was a 16-year-old boy was Thomas McBain, the policeman father of John and Michael McBain. Paige also was connected to the death, since she was the doctor in the operating room the night that he was brought in for surgery and had been drinking. Much later, David and Paige would learn that Spencer had set both of them up: Spencer was the one who actually shot Thomas McBain, and he murdered Mr. McBain in the hospital after his successful operation.

David headed to Thailand for clues on Margaret's disappearance and was shocked to find her alive and well, but with no memory of her baby or her life in Llanview. John and Natalie encountered David and Margaret there, and together the four of them returned to Llanview. Just as Spencer gave Todd a court-ordered lethal injection, John showed up with Margaret and shocked everyone. Blair pleaded with Spencer to resuscitate Todd, which he did. Margaret later regained her memory but was killed in a car accident before she could tell police about what Spencer had done. Blair felt horrible about not believing Todd and set out to prove her suspicious that Spencer had been behind framing Todd. She pretended to be in love with Spencer and even accepted his marriage proposal. Eventually she gained enough evidence to prove that Spencer was guilty and Spencer was arrested.

While in jail, Spencer confronted Asa Buchanan with his belief that he was Asa's illegitimate son from an affair with Emma Bradley, who was one of Renee Divine's bordello girls back in Nevada. On her deathbed, Emma had told Spencer that Asa was his biological father, not her late husband Ned Truman. But after a DNA test proved Spencer was not Asa's son after all, Spencer seemed to suffer a psychological breakdown. He entered an insanity plea and fooled court-appointed psychiatrist Marty Saybrooke into believing that he was unfit to stand trial. A vengeful Todd kidnapped Spencer and took him hostage, torturing him for information on the whereabouts of his son with Margaret. When Blair found out where Todd was hiding Spencer, she got in the middle of a fight between the two men and both Spencer and Blair ended up falling off the roof of a warehouse. While in the hospital recovering from their injuries, Spencer became more delusional and began to see visions of Blair in his hospital room. Spencer killed his lawyer and snuck in to Blair's room, where he drugged her and performed a wedding ceremony. Just as he was about to rape Blair, someone came in the room and stabbed him to death with a pair of scissors.

David confessed to the crime, having been promised $10 million by Asa to kill Spencer, but David was released when it was proven that he was innocent. Later, Lindsay Rappaport was arrested for Spencer's murder and confessed that she had killed him to keep Michael and Marcie McBain from losing their adopted son to his real father, Todd Manning, should Spencer ever reveal the truth.