BACKGROUND The objective of the current study was to identify mediators of the effects of a combined resistance and aerobic exercise program on perceived physical and general health in men undergoing androgen deprivation therapy for prostate cancer. METHODS In total, 57 patients with prostate cancer undergoing androgen deprivation therapy were randomly assigned to 12 weeks of resistance and aerobic exercise or usual care. The outcome measures of physical and general health were assessed by standardized questionnaires. Linear regression analyses were conducted on the residual change scores of the variables. The mediating effects of fatigue, muscle strength, and functional performance on the intervention's effect on physical and general health were examined using the product of coefficients method. Bootstrapping was used to calculate the 95% confidence intervals (95% CIs). RESULTS The exercise intervention was found to significantly improve physical (beta, 5.03; 95% CI, 1.01-9.04) and general health (beta, 12.89; 95% CI, 2.24-23.54). Upper body muscle strength and walking speed significantly mediated the intervention effect on physical health (beta, 2.65; 95% CI, 0.64-5.54), accounting for 53% of the total effect. Walking speed and fatigue were found to be mediators in the intervention effect on general health (beta, 7.52; 95% CI, 2.16-16.92), accounting for 51% of the total effect. CONCLUSIONS The intervention effects on physical and general health were explained by different mediating mechanisms. Walking speed mediated the intervention effect on both physical and general health. The intervention effect on physical health was further mediated by upper body strength, whereas the effect on general health was mediated by fatigue. © 2013 American Cancer Society.