The incidence of hepatocellular carcinoma (HCC) is much higher in men than in women. Several experiment and epidemiological studies have suggested that estrogen might play an inhibitory role in the development of HCC. Because isoflavones have a similar structure as 17beta-estradiol and appear to have an anti-estrogenic effect in women and estrogenic effect in men, we hypothesized that the effect of isoflavones on HCC differs by sex. We investigated the association between isoflavones (genistein and daidzein) and soy products and HCC in Japan in a population-based prospective study in 19,998 Japanese (7,215 men and 12,783 women) aged 40-69 years. During 11.8 years of follow-up, 101 subjects (69 men and 32 women) were newly diagnosed with HCC. Case patients were grouped according to consumption of isoflavones and soy products and stratified by hepatitis virus infection. Hazard ratios (HRs) and 95% confidence intervals (CIs) for HCC were calculated by Cox proportional-hazards modeling. In women, genistein and daidzein were dose-dependently associated with an increased risk of HCC, with multivariable HRs for the highest versus lowest tertile of 3.19 (95%CI = 1.13-9.00, p(trend) = 0.03) and 3.90 (95% CI = 1.30-11.69, p(trend) = 0.01), respectively. No association between isoflavones and HCC was observed in men. These results persisted when analysis was restricted to subjects positive for either or both hepatitis C and B virus. In conclusion, isoflavone consumption may be associated with an increased risk of HCC in women. Women with hepatitis virus infection may be advised to abstain from isoflavone consumption. Further studies are warranted to confirm these findings.