To identify factors that might be useful as prognostic indexes for the risk of hepatocellular carcinoma in Italian patients with genetic hemochromatosis, 152 homozygotes were studied prospectively for 1 to 229 mo. Factors that were considered in estimating the risk of developing hepatocellular carcinoma were age, sex, cirrhosis (Child class), HBsAg, antibodies to HBsAg, antibodies to HBcAg, hepatitis C antibodies, alcohol abuse and the amount of iron removed during therapeutic phlebotomy to produce iron depletion. At diagnosis, cirrhosis was present in 97 patients and absent in 55. During follow-up, hepatocellular carcinoma developed in 28 of the 97 patients with cirrhosis but in none of those without. Among patients with cirrhosis, the cumulative probability of being free of hepatocellular carcinoma at 10 yr was 70%. For patients with and without HBsAg the probabilities of being free of liver cancer at 10 yr were, respectively, 54% and 75%; for those with and without history of alcoholism, 58% and 78%; and for those younger and older than 55 yr, 90% and 54%. In patients with cirrhosis, multivariate analysis using proportional-hazards (Cox) regression found that the only factors contributing significantly to the estimation of a prognostic index were age, presence of HBsAg and alcohol abuse. Age over 55 yr increased the relative risk of hepatocellular carcinoma 13.3-fold (p < 0.001), the presence of HBsAg increased it 4.9-fold (p < 0.02) and alcohol abuse increased it 2.3-fold (p < 0.04). Homozygotes for genetic hemochromatosis with cirrhosis who were older than 55 yr had a history of alcohol abuse and were positive for HBsAg at the time of diagnosis had a 150 times higher relative risk of hepatocellular carcinoma. (HEPATOLOGY 1994;20:1426-1431.)