Experimental and clinical evidence indicates that estrogens have a relevant role in the pathogenesis of cancer of hormone-sensitive organs. Estrogen receptors (ERs) are present in liver cells. Normal liver expresses almost exclusively wild-type ERs derived from the full-length transcript of the gene. During progression of liver disease to hepatocellular carcinoma, variant forms of ERs have been demonstrated that greatly influence the course of the disease and the possibility of palliative treatment. Peritumoral cirrhotic tissue of patients with hepatocellular carcinoma, especially males, expresses a variant form of ER (vER) with an exon 5 deletion. In hepatocellular carcinoma, vER largely predominates and sometimes becomes the only form expressed. That the occurrence of vER alone is limited almost exclusively to males suggests that it could be one of the molecular events that eventually lead to the preferential development of hepatocellular carcinoma in males. In addition, the presence of vER appears most frequently in patients infected with the hepatitis B virus. The growth rate of hepatocellular carcinoma in patients with vER is also significantly higher than that in patients with tumors expressing wtER.