Evidence for a relation between physical activity and renal cell cancer has been inconsistent. The authors examined physical activity in relation to renal cell cancer in a large, prospective US cohort study of 482,386 participants (289,503 men and 192,883 women) aged 50–71 years at baseline (1995–1996). At baseline, participants reported their frequency of exercise of at least 20 minutes' duration, intensity of daily routine activity, and frequency of physical activity during adolescence. During 8.2 years of follow-up (through December 2003), 1,238 cases of renal cell cancer were ascertained. In multivariate Cox regression models adjusted for renal cell cancer risk factors, the authors observed that current exercise, routine physical activity, and activity during adolescence were associated with a reduced risk of renal cell cancer. The multivariate relative risks for the highest activity level as compared with the lowest were 0.77 (95% confidence interval (CI): 0.64, 0.92; ptrend = 0.10) for current exercise, 0.84 (95% CI: 0.57, 1.22; ptrend = 0.03) for routine physical activity, and 0.82 (95% CI: 0.68, 1.00; ptrend = 0.05) for activity during adolescence. The authors conclude that increased physical activity, including activity during adolescence, is associated with reduced risk of renal cell cancer.