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 (β = 0.17, p<0.01), as well as each of the respective subscales (β = 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 (β = 0.27), cancer worry (β = 0.36), cognitive function (β = 0.32), body appearance (β = 0.29), and social function (β = 0.27) (all p's<0.05). Among adult survivors of childhood cancer, LTPA was only significantly associated with physical function (β = 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. Copyright © 2009 John Wiley & Sons, Ltd.