BACKGROUND: Childhood cancer survivors are at risk for adverse psychological outcomes. Whether exercise can attenuate this risk is unknown. METHODS: In total, 6199 participants in the Childhood Cancer Survivor Study (median age, 34.3 years [range, 22.0-54.0 years]; median age at diagnosis, 10.0 years [range, 0-21.0 years]) completed a questionnaire assessing vigorous exercise and medical/psychological conditions. Outcomes were evaluated a median of 7.8 years (range, 0.1-10.0 years) later and were defined as: symptom level above the 90th percentile of population norms for depression, anxiety, or somatization on the Brief Symptom Inventory-18; cancer-related pain; cognitive impairment using a validated self-report neurocognitive questionnaire; or poor healthrelated quality of life. Log-binomial regression estimated associations between exercise (metabolic equivalent [MET]-hours per week −1 ) and outcomes adjusting for cancer diagnosis, treatment, demographics, and baseline conditions. RESULTS: The prevalence of depression at follow-up was 11.4% (95% CI, 10.6%-12.3%), anxiety 7.4% (95% CI, 6.7%-8.2%) and somatization 13.9% (95% CI, 13.0%-14.9%). Vigorous exercise was associated with lower prevalence of depression and somatization. The adjusted prevalence ratio for depression was 0.87 (95% CI, 0.72-1.05) for 3 to 6 MET hours per week −1 , 0.76 (95% CI, 0.62-0.94) for 9 to 12 MET-hours per week −1 , and 0.74 (95% CI, 0.58-0.95) for 15 to 21 MET-hours per week −1 . Compared with 0 MET hours per week −1 , 15 to 21 MET-hours per week −1 were associated with an adjusted prevalence ratio of 0.79 (95% CI, 0.62-1.00) for somatization. Vigorous exercise also was associated with less impairment in the physical functioning, general health and vitality (P trend < .001), emotional role limitations (P trend = .02), and mental health (P trend = .02) domains as well as higher cognitive function in the domains of task completion, organization, and working memory (P < .05 for all), but not in the domain of cancer pain. CONCLUSIONS: Vigorous exercise is associated with less psychological burden and cognitive impairment in childhood cancer survivors. Cancer 2019;125:3059-3067.