Colon cancer incidence rates have been rapidly increasing in Shanghai, China, for reasons still unclear. Low physical activity is a known risk factor for colon cancer. The authors examined the effects of physical activity, particularly commuting physical activity, and its joint effects with body mass index on colon cancer risk in a population-based, case-control study. The study included 931 incident colon cancer patients and 1,552 randomly selected controls in Shanghai between 1990 and 1993. Colon cancer risk was significantly reduced among subjects with high commuting physical activity (odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.27, 0.87 for men; OR = 0.56, 95% CI: 0.21, 0.91 for women), particularly among those who had high commuting physical activity for at least 35 years (OR = 0.34, 95% CI: 0.09, 0.76 for men; OR = 0.31, 95% CI: 0.07, 0.72 for women). Commuting physical activity significantly modified the risk conferred by high body mass index, with the highest risk observed among those at the highest quintile of body mass index and the lowest activity level (OR = 6.43, 95% CI: 1.82, 8.54 for men; OR = 7.42, 95% CI: 2.84, 10.01 for women). Our results suggest that regular and frequent physical activity over a long period of time protects from colon cancer and significantly modifies the body mass index-associated risk.