Objective: The impact of childhood cancer on future quality of life (QoL) in survivors is unclear. Current studies focus on comparing outcomes to healthy peers and identifying related treatment and demographic variables, but a shift in our approach is necessary. This study is guided by the Wilson and Cleary Model (WMC) and seeks to identify longitudinal predictors of QoL in adolescent survivors of cancer that explain variance in QoL beyond the impact of treatment and demographic variables. Methods: The Childhood Cancer Survivor Study (CCSS) is a multi-institutional longitudinal study following a cohort of childhood cancer survivors. This study focuses on the CCSS cohort (N = 305) who completed the baseline survey in 1994 and the Teen survey in 2001. The baseline survey assessed parent-report of child’s psychological and physical symptoms, functional status, and health perceptions. The Teen survey utilized the Child Health and Illness Profile – Adolescent Edition (CHIP-AE), a self-report measure assessing QoL in six domains: achievement, resilience, satisfaction, discomfort, disorders, and risk. The primary hypothesis was that psychological and physical symptoms, functional status impairment, and health perceptions as rated by parents at baseline would predict variance in quality of life as rated by adolescents at follow-up after adjusting for demographic and treatment-related variables. Six separate hierarchical regressions were analyzed for each of the QoL domains. Results: The main hypothesis was supported. For each QoL outcome, a significant amount of variance was predicted: achievement, F (6, 259) = 8.90, p < .001, adjusted R2 = .152, resilience, F (12, 209) = 3.47, p < .001, adjusted R2 = .118, satisfaction, F (6, 265) = 8.73, p < .001, adjusted R2 = .146, discomfort, F (7, 273) = 6.75, p < .001, adjusted R2 = .126, disorders, F (9, 212) = 6.47, p < .0001, adjusted R2 = .182, and risk, F (7, 238) = 4.81, p < .001, adjusted R2 = .098. Furthermore, for all outcomes, psychological and physical symptoms, functional status impairment, and health perceptions predicted variance above and beyond the impact of demographic and treatment variables. These factors accounted for an additional 9.5% of the variance in the achievement domain, 6.2% for resilience, 10.8% for satisfaction, 6.5% for discomfort, 12.4% for disorders, and 6.1% for risk. Conclusions: Results suggest that psychological and physical symptoms, functional status and health perceptions should be assessed and targeted in interventions for childhood cancer survivors to promote future positive QoL. Future studies need to continue identifying factors related to positive long-term functioning in diverse samples of childhood cancer survivors.