The aim of the current investigation was to evaluate the applicability of the Self-Regulation Model (SRM) for representing quality of life (QOL) in adolescents with chronic illness. Participants included 48 adolescents with chronic medical conditions, as well as 53 parents of adolescents with medical conditions. Measures included parent and adolescent reports of the adolescents’ QOL, illness representations, and coping/stress responses. Correlational analyses indicated that multiple coping/stress responses and illness representations were associated with lower QOL. Only adolescents’ reports of perceived treatment control were significantly associated with higher QOL. In total, 64% of the variance in QOL was accounted for by illness representations and coping/stress responses based on the adolescent self-reported data. Mediational analyses revealed indirect effects of illness representation on QOL. Given the current data, the SRM appears to be an adequate representation for adolescents with chronic medical conditions. Directions for future research and intervention development are indicated.