Soy isoflavones and estrogen related genes may play a major role in the etiology of prostate cancer. This study examined whether the genetic polymorphisms of estrogen receptors (ESR-alpha and ESR-beta) and cytochrome P450 19A1 (CYP19A1) modified the protective effect of isoflavones against prostate cancer. One hundred and eighty cases and 177 controls were selected from three geographic areas of Japan. The odds ratio for more than or equal to 60 versus less than 60 mg/day of the intake of isoflavones was 0.63 (95% confidence interval=0.41-0.96). The TTTA long repeat was significantly associated with an increased risk (odds ratio=1.76, 95% confidence interval=1.15-5.70). The interaction between the polymorphisms and the intake of isoflavones on prostate cancer risk was analyzed by the multifactor dimensionality reduction method. The combination of the TTTA long repeats and the minor alleles of rs10046 in CYP19A1 and rs2077647 in ESR-alpha was a high risk for prostate cancer despite greater than or equal to 60 mg isoflavones/day. The combination of the TTTA short repeat and those homozygous for the major allele of rs10046 in CYP19A1 was low risk despite less than 60 mg isoflavones/day. In conclusion, the findings of this case-control study suggest that the protective effect of isoflavones may differ between the genotypes of estrogen related genes.