Obesity has been reported to increase the risk of colon cancer, especially in men. The authors examined this relation in the American Cancer Society's Cancer Prevention Study II, a nationwide mortality study of US adults. After 12 years of follow-up, 1,616 deaths from colon cancer in women and 1,792 in men were observed among 496,239 women and 379,167 men who were cancer free at enrollment in 1982. The authors used Cox proportional hazards analyses to control for effects of age, race, education, smoking, exercise, alcohol, parental history of colon cancer, fat intake, vegetable and grain intake, aspirin use and, in women, estrogen replacement therapy. In men, death rates from colon cancer increased across the entire range of body mass index (BMI). The rate ratio was highest for men with BMI > or =32.5 (rate ratio (RR) = 1.90, 95% confidence interval (CI): 1.46, 2.47) compared with men with BMI between 22.00 and 23.49. In women, a weaker association was seen in the three BMI categories of 27.5-29.9 (RR = 1.26, 95% CI: 1.03, 1.53), 30.0-32.4 (RR = 1.37, 95% CI: 1.09, 1.72), and > or =32.5 (RR = 1.23, 95% CI: 0.96, 1.59). These prospective data support the hypothesis that obesity increases the risk of colon cancer death and that the relation is stronger and more linear in men than in women.