Technically not one of The 4400 returnees (she was still in the womb at the time), Isabelle Tyler (Megalyn Echikunwoke) is the daughter of Richard and Lily Tyler. Even while in the womb Isabelle proved to be very powerful, and as an infant she used her abilities to protect but also manipulate her parents. It was her blood alone that was able to save the 4400 when their lives were threatened by the promicin inhibitor.

Isabelle instantaneously jumped from being a toddler to a young woman, a dramatic transformation that also caused her mother Lily to age into an old woman. But Isabelle was not prepared to take her own life, thereby facilitating Lily's death. Isabelle struggled with her rapid maturation, turning to Shawn Farrell for guidance and eventually become romantically involved with him. She was torn between her feelings for Shawn and her destiny to destroy the 4400, which according to Matthew Ross was the reason she was given limitless abilities.

She began to assert her own will, killing Matthew and executing Nova Group members who'd attacked Shawn. Declaring that the fate of humanity was at stake, she convinced Shawn to marry her. The wedding was called off, however, thanks to the surprise reappearance of Jordan Collier. When Collier ordered her out of the 4400 Center, Isabelle turned to Dennis Ryland, allowing his researchers to extract her promicin in order to develop a supersoldier army.

When the promicin she donated was stolen, Isabelle tortured Shawn for information about its whereabouts. When she arrived at the location with Ryland and the supersoldiers, they walked right into a trap. Isabelle managed to escape death and went on a murderous spree at the 4400 Center in an attempt to draw Collier out. Instead, she was confronted by NTAC agents Tom Baldwin and Diana Skouris. But it was her father Richard who ultimately ended the rampage, injecting Isabelle with a syringe that took away her abilities. The confrontation left her injured, powerless, and in NTAC custody.