Heavy use of analgesics, particularly over-the-counter (OTC) products, has long been associated with chronic renal failure. Most of the earlier reports implicated phenacetin-containing analgesics as the risk factor. Since the early 1980s. several case-control studies have reported associations between chronic renal failure and use of other forms of analgesics, including acetaminophen, aspirin, and other non-steroidal antiinflammatory drugs (NSAIDs). Findings from these studies, however. should be interpreted with caution because of a number of inherent limitations and potential biases in the study design and data collection procedures. These limitations include: failure to identify patients early enough in the natural history of their disease to collect reliable information on analgesic use at an etiologically relevant time period; selection bias due to incomplete identification of subjects or low response rates; selection of cases and controls from different population bases; failure to employ survey techniques to improve reliability of recall of analgesic use; failure to collect detailed information on analgesic use such as year started and ended and reasons for switching analgesics; lack of standardization in the definition of regular analgesic use; and failure to adjust for phenacetin use and other confounding factors when assessing associations with analgesics other than those containing phenacetin. It is our hope that this review of study design limitations will lead to improvements in future studies of chronic renal failure risk. Since use of analgesics is widespread and new OTC products are introduced frequently, the potential impact of these drugs on the development of chronic renal failure may be significant, thus warranting continued evaluation of these products for any renal toxicity.