To examine the use of analgesics as a cause of chronic renal disease, we performed a multicenter case-control study of 554 adults with newly diagnosed kidney disease (serum creatinine, greater than or equal to 130 mumol per liter [1.5 mg per deciliter]) and 516 matched control subjects selected randomly from the same area of North Carolina. Histories of use of analgesics (phenacetin, acetaminophen, and aspirin) were obtained by telephone interview with the patients or their proxies. Daily users of analgesics had significantly more renal disease than infrequent users (odds ratio, 2.79; 95 percent confidence interval, 1.85 to 4.21). The risk of renal disease was highest in daily users of phenacetin (odds ratio, 5.11; confidence interval, 1.76 to 14.9, after adjustment for the effects of other analgesics). The risk of renal disease was also increased in daily users of acetaminophen; after adjustment for the use of aspirin and phenacetin, the odds ratio was 3.21 (confidence interval, 1.05 to 9.80). There was no increased risk in daily aspirin users (adjusted odds ratio, 1.32; confidence interval, 0.69 to 2.51). The risks with daily use of either phenacetin or acetaminophen changed little after adjustment for diabetes, hypertension, and the indication for analgesic use. We conclude that the long-term, regular use of phenacetin may increase the risk of chronic renal disease. The long-term, daily use of acetaminophen, the major metabolite of phenacetin, is associated independently with an increased risk of chronic renal disease. We could find no increased risk in daily users of aspirin.