Experimental studies suggest that NSAIDs could reduce prostate cancer risk. Results of observational studies on the relation between NSAIDs and prostate cancer risk have, however, been inconsistent. Moreover, none has addressed the issues of dosage, duration and timing of exposure. In a population-based, age-matched case-control study, we measured the association between prostate cancer risk and NSAIDs defined in terms of mean daily dose, cumulative duration and timing of exposure. Eight-year drug exposure history was obtained from the Quebec health insurance system database. Parallel analyses were performed for aspirin and NSAIDs other than aspirin. We controlled for detection bias and assessed the potential impact of protopathic bias. Analyses were performed with conditional logistic regression. Among the 2,221 cases and 11,105 controls, there was a negative trend between cumulative duration of aspirin use and prostate cancer risk (p = 0.0009). Also, exposure to a mean daily dose of aspirin of at least 80 mg, maintained throughout the entire 8 years of follow-up, was associated with an 18% reduction in prostate cancer risk (OR = 0.82, 95% CI 0.71-0.95). In more recent users of such a dose, the risk reduction was 7%. However, 1 year after the end of a 7-year regular aspirin exposure, no residual protective effect persisted. No association was observed between prostate cancer risk and exposure to NSAIDs other than aspirin. The results suggest that long-term and regular use of aspirin, at a dosage beneath that usually recommended for an anti-inflammatory effect, may prevent prostate cancer. Copyright 2003 Wiley-Liss, Inc.