OBJECTIVE: To prospectively investigate the relationship between physical activity and Parkinson disease (PD). METHODS: We evaluated physical activity in relation to PD among 213,701 participants of the NIH-AARP Diet and Health Study cohort. Physical activities over 4 periods (ages 15-18, 19-29, and 35-39, and in the past 10 years) were noted in 1996-1997, and physician-diagnosed PD was reported on the 2004-2006 follow-up questionnaire. Only cases diagnosed after 2000 (n = 767) were included in the analyses. RESULTS: Higher levels of moderate to vigorous activities at ages 35-39 or in the past 10 years as reported in 1996-1997 were associated with lower PD occurrence after 2000 with significant dose-response relationships. The multivariate odds ratios (OR) between the highest vs the lowest levels were 0.62 (95% CI confidence interval [CI] 0.48-0.81, p for trend 0.005) for ages 35-39 and 0.65 (95% CI 0.51-0.83, p for trend 0.0001) for in the past 10 years. Further analyses showed that individuals with consistent and frequent participation in moderate to vigorous activities in both periods had approximately a 40% lower risk than those who were inactive in both periods. Moderate to vigorous activities at earlier ages or light activities were not associated with PD. Finally, the association between higher moderate to vigorous physical activities and lower PD risk was demonstrated in a metaanalysis of prospective studies. CONCLUSIONS: Although we cannot exclude the possibility that less participation in physical activity is an early marker of PD, epidemiologic evidence suggests that moderate to vigorous exercise may protect against PD.