The etiologic role of physical activity in prostate cancer development is unclear. We assessed the association between lifetime total physical activity and prostate cancer risk in a Swedish population-based case-control study comprising 1,449 incident prostate cancer cases and 1,118 unaffected population controls. Information regarding physical activity was obtained via a self-administered questionnaire assessing occupational, household, and recreational activity separately at various ages throughout an individual's lifetime. Clinical data (TNM-classification, Gleason sum and PSA) was obtained from linkage to the National Prostate Cancer Registry. Overall, we observed no association between lifetime total physical activity and prostate cancer risk (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 0.77-1.41 for > or =49.7 vs. <41.9 metabolic equivalent-hours per day). There was a significantly increased risk of prostate cancer in the most active men compared with the least active men in household (OR = 1.44, 95% CI = 1.08-1.92) and recreational physical activity (OR = 1.56, 95% CI = 1.16-2.10). Comparing the most active with the least active men, total physical activity was not associated with either localized disease (OR = 0.95, 95% CI = 0.67-1.34) or advanced disease (OR = 1.19, 95% CI = 0.83-1.71). These findings do not support the hypothesis that physical activity uniformly protects against prostate cancer development.