We conducted a nested, matched case-control study in the General Practice Research Database (GPRD) to assess whether acetaminophen use is associated with renal or bladder cancer. We matched 109 cases of renal cancer and 189 cases of bladder cancer with up to 4 controls each by age, sex, general practice, duration of drug history in the GPRD, and index date. We found that use of acetaminophen from 1 to 5 years before the index date was associated with an increased risk of renal cancer, with a direct relation between risk and number of prescriptions and an adjusted odds ratio of 2.3 (95% CI 1.0-5.3) for subjects with 20 or more prescriptions. There was no evidence for an increase in risk of bladder cancer with acetaminophen use. We found no association between use of non-steroidal anti-inflammatory drugs and either renal or bladder cancer. These results support previous findings from our group and are consistent with a slight increase in the risk of renal cancer, but not bladder cancer, with heavy acetaminophen use.