Cyclooxygenase-2 (COX-2) converts arachidonic acid to prostaglandins, which are important mediators of cell proliferation and inflammation. Evidence indicates that COX-2 plays a role in carcinogenesis and that it is over-expressed in prostate tumours. We investigated the role of COX-2 variants in prostate cancer in a case-control study of South African Coloured men, consisting of 151 cases and 134 controls. The genotype frequencies of four single-nucleotide polymorphisms (SNPs) in the COX-2 promoter were initially determined in 50 control subjects. One SNP, rs20417 (-899G>C), was monomorphic and excluded from further investigation. Three SNPs, rs3918304 (-1285A>G), rs20415 (-1265C>T) and rs5270 (-297C>G), were genotyped in all the case patients and control subjects. The -1285 G-allele and -1265 T-allele were associated with increased risk of prostate cancer [odds ratio (OR) = 3.53; confidence interval (CI) = 2.14-5.90; P < 0.0001 and OR = 3.01; CI = 1.82-5.02; P < 0.0001] after adjusting for age. Haplotype GTC conferred increased risk of prostate cancer in South African Coloured men (OR = 3.54 versus ACC; CI = 2.12-5.92; P < 0.0001). These findings in conjunction with findings in other populations of African descent might suggest a common causal variant for prostate cancer in COX-2, or a variant in a nearby gene.