Melissa arrived in Port Charles in January 2001. Years ago, Melissa's younger brother Leo was working for Joseph Sorel. Roy had befriended Leo and he and Melissa had been romantically involved, but Roy eventually betrayed them by turning Leo over to the FBI. Leo was imprisoned, where he was later killed by one of Sorel's men. Melissa wasn't able to forgive Roy at the time, and their relationship ended.
However, after enough time had gone by, Melissa realized she was still in love with Roy, so she came to Port Charles to see him. She got a job at the hospital as a nurse, working alongside Bobbie Spencer. Initially, upon discovering that Roy was with Bobbie, Melissa tried to respect their relationship. But when Bobbie's jealousy and suspicions caused her and Roy to break up, Melissa decided to go for Roy. Roy realized he had feelings for her as well, and the two started to rekindle their relationship.
When Sorel was murdered in his hospital bed, Melissa and Roy were both immediate suspects because of their hate for him. However, it soon became clear that Sonny Corinthos was probably the responsible party. However, Sonny wasn't the culprit; Angel Ellis, Sorel's daughter, was.
After Edward Quartermaine faked being mugged by Zander Smith, he became friendly with Nurse Bedford. However, his family cried foul after he rewrote his will, leaving half of his fortune to Melissa. When Edward had a heart attack after a visit with Melissa, his family suspected Melissa and she was relieved of duties at GH. When it became apparent that Melissa had nothing to do with Edward's heart attack, she was reinstated. In the meantime, Roy became suspicious and began to investigate her past relationships with elderly and terminal patients. With Laura and Lucky Spencer's help, Roy discovered a long trail of patients who died while under her care. Even though Melissa convinced Edward to remove her from his will, Roy continued investigating her past. Roy discovered proof that Melissa had killed several patients, and planned to go to the police, even though Melissa begged him not to. When he didn't change his mind, she asked him how he felt doing to her what he had done to her brother. After Taggert arrived, Melissa calmly, almost peacefully recounted the many lives of the suffering she had ended. She asked Taggert if he could arrest someone who had done nothing but help those in pain die with dignity. He did, and as she was led away, Melissa reminded Roy again of how much he had betrayed her. Melissa was last seen being transferred to Chicago for trial, after refusing Bobbie and Scott's offer of help with her case.