To determine if the risk of hepatocellular carcinoma (HCC) is reduced by consumption of soya foods, we conducted a case-control study within a cohort of Japanese A-bomb survivors. We compared the prediagnosis consumption of isoflavone-rich miso soup and tofu to HCC risk, adjusting for hepatitis B (HBV) and C (HCV) viral infections, the major HCC risk factors in this population. The study included 176 pathologist-confirmed cases of HCC diagnosed in 1964–1988 and 560 controls who died of diseases other than liver cancer. We examined dietary information collected at least 2 years before diagnosis or death and tissue-based measures of viral hepatitis. Using logistic regression, crude ORs were 0.5 (95% CI 0.29–0.95) and 0.5 (95% CI 0.20–0.99) for high vs. low miso soup and tofu intake, respectively. Adjusting for year of birth, sex, HBV, HCV and other factors, the OR for miso soup was unchanged at 0.5 (95% CI 0.14–1.55), and miso results were similar when ORs were recalculated separately for earlier and later birth cohorts to assess consistency of results. The adjusted OR for tofu was 0.9 (95% CI 0.20–3.51). We also found a statistically significant (p < 0.0001) interaction between sex and HCV, with risk of HCC being substantially higher for women. We conclude that consumption of miso soup and other soya foods may reduce HCC risk. © 2005 Wiley-Liss, Inc.