BACKGROUND Few studies have evaluated the association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of idiopathic acute renal failure (ARF) in the general population. METHODS Population-based case-control study among persons in the Canadian province of Saskatchewan who received at least 1 NSAID prescription between January 1, 1982, and December 31, 1986. Health department databases were used for case detection, as the sampling frame for selecting controls (n = 1997), and as the primary source of information on drug use and comorbidity. A total of 306 hospital records were reviewed. Twenty-eight patients who were hospitalized fulfilled the diagnostic criteria for ARF. RESULTS The incidence rate of hospitalization for ARF among the general population not exposed to NSAIDs was 2 per 100000 person-years. Current exposure to NSAIDs, acetylsalicylic acid and other nephrotoxic drugs, male gender, increasing age, cardiovascular comorbidity, and recent hospitalization for disorders other than renal were found to be independent risk factors for ARF. Current NSAID users had an adjusted odds ratio for ARF of 4.1 (95% confidence interval, 1.5-10.8). The risk of ARF was especially high during the first month of use (odds ratio, 8.5). For prescribed dose, we found that users of high daily doses of NSAIDs experienced an odds ratio of 9.8 for ARF. CONCLUSIONS In the general population, hospitalizations for ARF were found to be a rare condition. The 4-fold increase in risk associated with NSAID use was dose-dependent and occurred especially during the first month of therapy. Concurrent comedication with other potentially nephrotoxic agents should be prescribed with care, especially in the elderly.