Increased body size and lack of physical activity are associated with increased risk of several cancers, but the relations of body mass index (BMI) and physical activity to bladder cancer are poorly understood. We investigated the associations between BMI, physical activity, and bladder cancer in the NIH-AARP Diet and Health Study, a prospective cohort of 471,760 U.S. men and women, followed from 1995 to 2003. During 3,404,642 person-years of follow-up, we documented 1,719 incident cases of bladder cancer. Compared with normal weight, obesity was associated with an up to 28% increased risk for bladder cancer. The multivariate relative risks of bladder cancer for BMI values of 18.5 to 24.9 (reference), 25.0 to 29.9, 30.0 to 34.9, and >or=35 kg/m2 were 1.0, 1.15, 1.22, and 1.28 (95% confidence interval, 1.02-1.61; P trend = 0.028). The association between BMI and bladder cancer was consistent among subgroups defined by gender, education, smoking status, and other potential effect modifiers. In contrast, physical activity showed no statistically significant relation with bladder cancer. After multivariate adjustment, including BMI, the relative risks of bladder cancer for increasing frequency of physical activity [0 (reference), <1, 1-2, 3-4, and >or=5 times a week] were 1.0, 0.85, 0.89, 0.91, and 0.87 (95% confidence interval, 0.74-1.02; P trend = 0.358), respectively. In conclusion, these findings provide support for a modest adverse effect of adiposity on risk for bladder cancer. In contrast, our results do not suggest a relation between physical activity and bladder cancer.