Genetic factors have been shown to play an important role in the etiology of osteoarthritis (OA). To elucidate the possible role of genetic variation in the estrogen receptors alpha and beta (ER-alpha, ER-beta) and androgen receptor (AR) genes with knee OA, the -1174(TA)(n), c.1092+3607(CA)(n), and c.172(CAG)(n) repeat polymorphisms of ER-alpha, ER-beta, and AR genes were studied. A case-control cohort of 158 patients with idiopathic knee OA and 193 controls were used. A significant difference was observed in the frequency distribution of -1174(TA)(9-25) and c.1092+3607(CA)(13-27) repeat polymorphisms of the ER-alpha and ER-beta genes between OA patients and controls (p<0.005 and p<0.0001, respectively). A significantly increased odds ratio (OR) for knee OA was observed in individuals having long alleles (LL) genotype for ER-alpha gene and LL and one short and one long allele (SL) genotypes for ER-beta gene compared to individuals with the short alleles (SS) genotype (95% CI 1.03-3.5; p=0.04 and CI 2.4-8.3 and 2.5-7.5; p < 0.001, respectively). When ORs were adjusted for various risk factors, it was observed that women with LL genotypes for ER-beta and AR genes showed significantly increased risk for OA development (p=0.002 and 0.001). An association between c.1092+3607(CA)(13-27) and c.172(CAG)(8-34) repeat polymorphisms of the ER-beta and AR genes and knee OA was found in individuals of Greek descent.