A recent meta-analysis showed that aspirin was associated with reduced prostate cancer risk. As anti-inflammatory medications lower PSA levels, whether these findings reflect reduced prostate cancer detection or lower prostate cancer risk is unknown. We tested the association between aspirin and nonaspirin NSAID use on prostate cancer diagnosis in REDUCE, where all men received biopsies at 2 and 4 years largely independent of PSA. REDUCE tested dutasteride for prostate cancer risk reduction in men with a PSA of 2.5 to 10.0 ng/mL and a negative prestudy biopsy. Experimental Design: We examined the association between aspirin, NSAIDs, or both and total, low-grade (Gleason < 7), or high-grade (Gleason -≥ 7) prostate cancer versus no prostate cancer using multinomial logistic regression among 6,390 men who underwent -≥ 1on-studybiopsy.Multivariableanalyseswereadjusted for age, race, geographic region, PSA, prostate volume, digital rectal examination, body mass index, treatment arm, smoking, alcohol, statins,hypertension,diabetes,andcardiovascular disease. Results: Overall, 3,169men(50%)were nonusers, 1,368 (21%) used aspirin, 1,176 (18%) used NSAIDs, and 677 (11%) used both. In unadjusted models, aspirin was associated with reduced prostate cancer risk (OR =0.85, P =0.036). In multivariable analyses, aspirin was associated with reduced total prostate cancer risk (OR =0.81, P = 0.015).Use of NSAIDs or NSAIDs and aspirin was not associated with total, low-grade, or high-grade prostate cancer, though allORs were <1(all P - 0.08). Therefore, wecreated a dichotomous variable of aspirin and/or NSAID users versus nonusers. On multivariable analysis, the use of aspirin and/or NSAIDs was significantly associated with decreased total (OR = 0.87, P = 0.030) and high-grade (OR= 0.80, P = 0.040), but not with low-grade, prostate cancer risk (OR =0.90, P =0.15). Results were similar in placebo and dutasteride arms. Conclusions: Among men with a negative biopsy, aspirin and/or NSAID use was associated with decreased prostate cancer risk. Additional studies are warranted. Clin Cancer Res; 21(4); 756 - 62.