Worldwide, primary hepatocellular carcinoma may be the most common cancer in men. Usually it occurs in association with cirrhosis or chronic hepatitis. In this article I present evidence that the majority of these cases are associated with, and probably caused by, persistent infection with hepatitis B virus. I also propose a model that describes the role of the hepatitis B virus in the pathogenesis of primary hepatocellular carcinoma. If persistent infection with hepatitis B virus is required for the development of most cases of primary hepatocellular carcinoma, prevention of such infections should prevent most cases of primary hepatocellular carcinoma. A vaccine against hepatitis B virus, prepared from surface antigen particles (HBsAg) harvested from the blood of hepatitis B virus carriers, has been safe and effective in preventing acute infection with hepatitis B virus in adult homosexual men. If it is equally safe and effective in young children, it will be administered widely to populations living in areas endemic for hepatitis B virus infections. Thereafter it may be possible to learn within five to 10 years whether the vaccine prevents chronic liver disease. If it does, it will be reasonable to conclude that it will also prevent primary hepatocellular carcinoma.