OBJECTIVE: Survivors of childhood cancer are at an increased risk for reduced quality of life (QOL), yet few studies have explored factors associated with improving health-related QOL (HRQOL) in this population. We thus explored the relationship between physical activity (PA) and HRQOL among survivors of childhood cancer. METHODS: A total of 215 survivors of childhood lymphoma, leukemia, and central nervous system cancers completed mailed surveys that elicited information regarding leisure-time PA (LTPA) measured in metabolic equivalents, HRQOL, and diagnostic and demographic factors. Correlations and adjusted regression models were used to explore the relationship between LTPA and HRQOL. RESULTS: In the total sample, modest, yet significant linear associations were observed between LTPA and overall HRQOL (beta=0.17, p<0.01), as well as each of the respective subscales (beta=0.11-0.23 and p's<0.05 to <0.001). Among adolescent survivors of childhood cancer, LTPA was significantly associated with overall HRQOL (beta=0.27), cancer worry (beta=0.36), cognitive function (beta=0.32), body appearance (beta=0.29), and social function (beta=0.27) (all p's<0.05). Among adult survivors of childhood cancer, LTPA was only significantly associated with physical function (beta=0.28, p<0.001). CONCLUSIONS: Significant associations exist between LTPA and HRQOL; however, the association was stronger and observed in more domains for adolescent survivors of childhood cancer. More research is needed to determine the antecedents and consequences of PA in this population.