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BACKGROUND. The causes of prostate cancer are poorly understood, but genetic factors may be more important than for many other malignancies, and dietary phytoestrogens may be protective. Because phytoestrogens bind tightly to the estrogen receptor-beta, we conducted an epiderniologic investigation of synergistic effects between phytoestrogen intake and estrogen receptor-beta gene polymorphisms. METHODS. We performed a population-based case-control study in Sweden. All participants reported their phytoestrogen intake and donated a blood sample. We identified four haplotype-tagging single nucleotide polymorphisms (htSNPs) and genotyped these htSNPs in 1314 prostate cancer patients and 782 controls. Odds ratios were estimated by multivariate logistic regression. Interactions between phytoestrogen intake and estrogen receptor-beta SNPs on prostate cancer risk were evaluated considering both multiplicative and additive effect scales. RESULTS. We found a significant multiplicative interaction (P = 0.04) between dietary intake of phytoestrogens and a promoter SNP in the estrogen receptor-beta gene (rs 2987983-13950), but not with any of the three other htSNPs (P = 0.11, 0.69, 0.85). Among carriers of the variant promoter alleles, we found strong inverse associations with increasing intake of total phytoestrogens (odds ratio for highest vs. lowest quartile = 0.43; P for trend < 0.001), isoflavonoids (odds ratio = 0.63; P for trend = 0.05), and coumestrol (odds ratio = 0.57; P for trend = 0.003). We found no association between phytoestrogens and prostate cancer among carriers homozygous for the wild-type allele (TT). CONCLUSIONS. Our study provides strong evidence that high intake of phytoestrogens substantially reduce prostate cancer risk among men with specific polymorphic variation in the promoter region of the estrogen receptor-beta gene.