We examined the association between occupational and leisure physical activity and colorectal cancer in a cohort of male smokers. Among the 29,133 men aged 50-69 years in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study,152 colon and 104 rectal cancers were documented during up to 12 years of follow-up. For colon cancer, compared with sedentary workers, men in light occupational activity had a relative risk (RR) of 0.60 [95% confidence interval (CI), 0.34-1.04], whereas those in moderate/heavy activity had an RR of 0.45 (CI, 0.26-0.78; P for trend, 0.003). Subsite analysis revealed a significant association for moderate/heavy occupational activity in the distal colon (RR, 0.21; CI, 0.09-0.51) but not in the proximal colon (RR, 0.87; CI, 0.40-1.92). There was no significant association between leisure activity and colon cancer (active versus sedentary; RR, 0.82; CI, 0.59-1.13); however, the strongest inverse association was found among those most active in both work and leisure (RR, 0.33; CI, 0.16-0.71). For rectal cancer, there were risk reductions for those in light (RR, 0.71; CI, 0.36-1.37) and moderate/heavy occupational activity (RR, 0.50; CI, 0.26-0.97; P for trend, 0.04), and no association for leisure activity. These data provide evidence for a protective role of physical activity in colon and rectal cancer.