Clinical and experimental evidence indicates that estrogens are involved in the control of hepatocyte proliferation both in normal and in neoplastic conditions. Thirty-two cirrhotic patients with unresectable or otherwise untreatable hepatocellular carcinoma were allocated to receive either tamoxifen (30 mg/day) or no treatment. The patients in the two groups were matched for age, male/female ratio, Child-Pugh class, approximate tumor volume (US and CT scan), and etiology of the underlying cirrhosis. Survival of the tamoxifen-treated patients (life-table, Wilcoxon-Breslow) was significantly prolonged (P = 0.0038), with 35% (vs 0%) survival at 12 months. No difference was observed between males and females or between alcoholic and nonalcoholic cirrhosis. In 40% of tamoxifen-treated patients, the levels of alpha-fetoprotein declined. In conclusion, the antiestrogen tamoxifen appears to be effective in the palliative treatment of hepatocellular carcinoma. An initial decline in alpha-fetoprotein levels may represent an early favorable prognostic sign.