||BACKGROUND: Whether physical activity has benefits against prostate cancer incidence or progression is unclear. Therefore, we assessed physical activity in relation to prostate cancer incidence, mortality, and Gleason histologic grade. METHODS: We used data from the Health Professionals Follow-up Study, a prospective cohort study, to determine the number of cases of incident, advanced (seminal vesicle invasion, metastasis, or fatal), fatal, and high-grade prostate cancer in a cohort of 47,620 US male health professionals, followed up from February 1, 1986, to January 31, 2000. RESULTS: During 14 years of follow-up, we documented 2892 new cases of prostate cancer, including 482 advanced cases (280 of which were fatal). For total prostate cancer, no association was observed for total, vigorous, and nonvigorous physical activity. In men 65 years or older, we observed a lower risk in the highest category of vigorous activity for advanced (multivariable relative risk, 0.33; 95% confidence interval, 0.17-0.62, for more than 29 vs 0 metabolic equivalent hours) and for fatal (relative risk, 0.26; 95% confidence interval, 0.11-0.66) prostate cancer. No associations were observed in younger men. Differential screening by prostate-specific antigen or a reduction in physical activity due to undiagnosed prostate cancer did not appear to account for the results. Among cases, men with high levels of physical activity were less likely to be diagnosed with poorly differentiated cancers (Gleason grade > or = 7). CONCLUSION: Although the mechanisms are not yet understood, these findings suggest that regular vigorous activity could slow the progression of prostate cancer and might be recommended to reduce mortality from prostate cancer, particularly given the many other documented benefits of exercise.