The etiology of prostate cancer (PC) remains mostly unknown, but increasing evidence suggests that chronic inflammation in the prostate is associated with an increased risk of PC. Epidemiological studies have suggested that use of nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against PC. Inborn variations in genes involved in the inflammatory response may modulate the risk of PC and interact with NSAIDs. The aims of this study were 1) to evaluate whether polymorphisms and haplotypes of the inflammation-related genes COX-2, Il1B, NFKB1, and PPARG are associated with risk of PC; 2) to investigate gene-environment interactions between polymorphisms and NSAID use; and 3) to examine whether the studied polymorphisms were associated with the aggressiveness of PC. The study population consisted of 370 cases of PC and 370 risk-set matched (age) controls nested within the prospective Danish "Diet, Cancer, and Health" cohort. Carriers of the variant deletion allele of NFKB1 -94ins/delATTG had a tendency toward a reduced risk of PC (incidence rate ratio (IRR), 0.73; 95% confidence interval (CI) 0.52-1.04). A lowered risk for PC was also found for carriers of variant allele NFKB1 -94ins/delATTG among non-users of NSAIDs (IRR 0.68; 95% CI 0.47-0.99), for non-aggressive disease (IRR 0.64; 95% CI 0.42-0.99), and among men with a body mass index above 30 kg/m(2) (IRR 0.56; 95% CI 0.27-1.16), although the latter estimate was based on small numbers. A similar pattern was seen for the variant C allele of the COX-2 +8473T→C polymorphism. No apparent association with PC was observed for the other studied polymorphisms. Our study did not indicate that chronic inflammation is a major risk factor for aggressive PC.