The impact of total physical activity level on cancer risk has not been fully clarified, particularly in non-Western, relatively lean populations. The authors prospectively examined the association between daily total physical activity (using a metabolic equivalents/day score) and subsequent cancer risk in the Japan Public Health Center-based Prospective Study. A total of 79,771 general-population Japanese men and women aged 45-74 years who responded to a questionnaire in 1995-1999 were followed for total cancer incidence (4,334 cases) through 2004. Compared with subjects in the lowest quartile, increased daily physical activity was associated with a significantly decreased risk of cancer in both sexes. In men, hazard ratios for the second, third, and highest quartiles were 1.00 (95% confidence interval (CI): 0.90, 1.11), 0.96 (95% CI: 0.86, 1.07), and 0.87 (95% CI: 0.78, 0.96), respectively (p for trend = 0.005); in women, hazard ratios were 0.93 (95% CI: 0.82, 1.05), 0.84 (95% CI: 0.73, 0.96), and 0.84 (95% CI: 0.73, 0.97), respectively (p for trend = 0.007). The decreased risk was more clearly observed in women than in men, especially among the elderly and those who regularly engaged in leisure-time sports or physical exercise. By site, decreased risks were observed for cancers of the colon, liver, and pancreas in men and for cancer of the stomach in women. Increased daily physical activity may be beneficial in preventing cancer in a relatively lean population.