The origin of the sex-associated differences in the progression of hepatitisC virus (HCV)-infected liver disease remains to be elucidated. This study was performed to assess possible risks of menopause and hepatic estrogen receptor (ER) levels for the development of hepatocellular carcinoma (HCC). Methods: One thousand and thirty-two consecutive HCC-patients with HCV-related cirrhosis were divided into two groups, based on the menopause-related age of 55 years. Liver tissues were obtained undergoing surgical resection of HCC and metastatic liver tumor. Results: The HCC subjects <55 years of age had a significantly lower female proportion (17.5%) than the subjects > 50 years of age (30.1%). Univariate analysis showed that HCV-related cirrhotic patients who developed HCC were more likely to have low hepatic levels of ER and copper-zinc superoxide dismutase (CuZn-SOD) protein, and a high hepatic level of a lipid peroxidation product, malondialdehyde(MDA). Logistic regression identified older age than 55 years of age (odds ratio [OR]: 7.4, 95% confidence interval [CI]: 2.8-19.1), male gender (OR: 3.5, 95% CI: 1.3-10.2), a decreased ER level (OR: 21.7, 95% CI: 8.8-55.7), and an increased MDA (OR: 8.3, 95% CI: 2.8-24.0) as the variables independently associated with the development of HCC in HCV-infected patients with cirrhosis. The study also suggested that menopause in women led to a lowering of hepatic ER levels. Conclusions: These findings suggest that increased lipid peroxidation and impaired SOD function in the liver may be associated with decreased hepatic ER levels in HCV-infected patients with cirrhosis and HCC, and that HCV-related cirrhotic women before menopause might have the ability to protect against developing HCC via hepatic ER.