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Acetaminophen is a metabolite of phenacetin, a drug that has been implicated as a causal agent in the development of renal and bladder cancer. We conducted matched case-control studies to estimate the risk of renal and bladder cancer among heavy users of acetaminophen, using data from Group Health Cooperative of Puget Sound. For the renal cancer study, we identified 222 incident cases diagnosed in the years 1980-1991 and 885 controls. For bladder cancer, we identified 504 cases and 2,009 controls. Exposure was defined according to the number of prescriptions for acetaminophen and acetaminophen-containing drugs filled at the Group Health Cooperative pharmacy. The relative risk estimate for renal cancer for subjects who filled 40 or more prescriptions was 2.6 [95% confidence limits (CL) = 1.1, 6.0], compared with the risk for subjects who did not fill any prescriptions for acetaminophen. We found only a small increased risk of bladder cancer among subjects with heavy acetaminophen exposure (odds ratio = 1.3; 95% CL = 0.6, 2.8).