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Large regional variations in bladder cancer rates have been observed for numerous decades in the United States and persist to date. We examined the incidence rates of bladder cancer by geographic region among U.S. male health professionals to determine whether diet or other lifestyle factors can account for variations observed. During 12 years of follow-up, 328 cases of bladder cancer were diagnosed in the Health Professionals Follow-up Study cohort. We inquired about diet, lifetime history of smoking, race, marital status, and other nondietary factors using mailed questionnaires. An elevated risk of bladder cancer was observed in the Northeast compared with the West [relative risk (RR) = 1.71, 95% confidence interval (CI) = 1.23-2.39], which was slightly attenuated after controlling for smoking (RR = 1.65, 95% CI = 1.18-2.30). Smoking patterns, diet, and other lifestyle factors could not account for all of the elevated bladder cancer risk in the Northeast. Bladder cancer risk was highest among men who had a long residency in the Northeast compared with a long residency in the West (RR = 1.77, 95% CI = 1.15-2.71, adjusted for smoking). Diet and other known characteristics do not appear to be responsible for the regional variations in bladder cancer rates in the United States.