The association between use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of prostate cancer remains controversial despite many observational epidemiological studies. We conducted a systematic meta-analysis of these studies to examine both the strength and the consistency of the association, and to explore sources of variability between studies. We searched 12 computerized literature databases for reports published before June 2008 and included any epidemiologic studies where the outcome was prostate cancer incidence or mortality, and the exposure was use of NSAIDs. Studies that met the inclusion criteria comprised 10 case–control and 14 cohort studies with a total of 24,230 prostate cancer cases. Studies that assessed the effect of aspirin use on total prostate cancer had a pooled odds ratio (POR) of 0.83 (95%CI: 0.77–0.89), whereas those that assessed the effect of aspirin on advanced prostate cancer had a POR of 0.81 (0.72–0.92). Studies that examined the effects of non-aspirin NSAIDs or all NSAIDs were less consistent but still suggestive of reduced risks. However, most reviewed studies were limited by exposure and disease misclassification, by inadequate information on dose and duration of use and by the possibility of screening and other biases. In conclusion, the epidemiologic evidence for a protective effect of aspirin and other NSAID use against prostate cancer is suggestive but not conclusive. There is a need for well-designed observational studies with adequate exposure measurements, accurate case definition, attention to latency effects, and careful adjustment for screening and other biases.