Background: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has consistently been associated with a reduced risk of colon cancer. Recent epidemiologic studies have suggested that the use of NSAIDs, particularly aspirin, may also be associated with a reduced risk of prostate cancer, but the evidence remains limited. Methods: We examined the association between NSAID use and prostate cancer incidence among 70 144 men in the American Cancer Society's Cancer Prevention Study II Nutrition Cohort. Information on NSAID use was obtained from a questionnaire completed at study enrollment in 1992–1993 and was updated using follow-up questionnaires in 1997 and 1999. We calculated rate ratios (RRs) and 95% confidence intervals (CIs) for prostate cancer incidence associated with NSAID use, adjusting for age and potential prostate cancer risk factors. Results: During follow-up from 1992–1993 through August 31, 2001, 4853 cases of incident prostate cancer were identified. Neither current aspirin use nor current use of NSAIDs (aspirin and other NSAIDs combined) was associated with prostate cancer risk, even at the highest usage level (60 or more pills per month). However, long-duration regular use (30 or more pills per month for 5 or more years) of NSAIDs was associated with reduced risk of prostate cancer (RR = 0.82, 95% CI = 0.71 to 0.94). Long-duration regular use of aspirin was also associated with reduced risk of prostate cancer (RR = 0.85, 95% CI = 0.73 to 0.99). The absolute rate of prostate cancer (standardized to the age distribution of study participants using 5-year age categories) was 1013 per 100 000 person-years among men who had never reported NSAID use, and 847 per 100 000 person-years among long duration regular NSAID users. Conclusions: These results support the hypothesis that long duration regular NSAID use is associated with modestly reduced risk of prostate cancer.