The relationship between physical inactivity, body mass index (BMI) (wt[kg]/ht[m]2), and pattern of adipose distribution with risk of colorectal adenomas (precursors of cancer) was examined in 13,057 female nurses in the United States, 40 to 65 years of age in 1986, who had an endoscopy between 1986 and 1992. From 1986 to 1992, 439 participants were newly diagnosed with adenomas of the distal colorectum. After controlling for age, prior endoscopy, parental history of colorectal cancer, smoking, aspirin, and intakes of animal fat, dietary fiber, folate, methionine, and alcohol, physical activity was associated inversely with risk of large (> or = 1 cm) adenomas in the distal colon (relative risk [RR] = 0.57, 95 percent confidence interval [CI] = 0.30-1.08, comparing high and low quintiles of average weekly energy expenditure from leisure-time activities; P trend = 0.05). Much of the benefit came from activities of moderate intensity such as brisk walking. In addition, BMI was associated directly with risk of large adenomas in the distal colon (multivariate RR = 2.21 [CI = 1.18-4.16], P trend = 0.0001, for BMI > or = 29 cf < 21 kg/m2). Waist circumference and the waist-to-hip ratio (WHR) were not related significantly to adenoma independently of BMI, but women with both a high BMI and high WHR were at greater risk of large colon adenoma (multivariate RR = 1.99, CI = 0.98-4.05) than women with high BMI but relatively low WHR (multivariate RR = 1.35, CI = 0.61-2.97). BMI was not related to small (< 1 cm) adenoma risk but physical activity had an inverse association with small adenomas in the distal colon (multivariate RR = 0.68, CI = 0.40-1.15, P trend = 0.03). The relationships between BMI or physical activity were considerably weaker and inconsistent for rectal adenomas. These results, in women, support an inverse association between physical activity and occurrence or progression of adenomas in the distal colon; obesity is associated with an elevated risk of large adenomas.