Alcohol has been known to be associated with an increased risk of cancer. We investigated the characteristics of hepatocellular carcinoma (HCC) in heavy drinkers with negative serum markers for viral hepatitis (non-B, non-C) to determine whether ethanol enhances the development of HCC in Japanese patients with or without serum markers for viral hepatitis. Among the 432 HCC cases seen at our hospital between 1995 and 2000, 26 patients had negative serum markers (non-B, non-C) and were heavy drinkers. The mean patient age at the time of HCC diagnosis was [Formula: see text] years. The mean total ethanol intake was [Formula: see text] kg. Most of the patients also had liver cirrhosis (LC), although the frequency was significantly higher in non-B, non-C, heavy drinkers HCC cases than in non-B, non-C, non-alcoholic HCC cases. Among the hepatitis C virus (HCV)-positive cases, the mean age at the time of HCC diagnosis was lower in heavy drinkers; this trend was not seen in HBV-positive cases. In HCC cases with heavy drinking, a high frequency of gastrointestinal (oropharynx, esophagus, stomach, colon and anal) cancers was seen. As for the aldehyde dehydrogenase-2 (ALDH2) genotype, the frequency of normal homozygotes was 87.5% in heavy drinkers with HCC and the frequency of heterozygotes was 12.5%; the frequency of heterozygotes was 58.3% in alcoholics with esophageal cancer. More than half of the non-B, non-C, heavy drinkers HCC cases had a normal range of serum alpha-fetoprotein (AFP) levels. These results indicate that heavy drinking enhances HCV-related hepatocarcinogenesis. Whether or not ethanol is directly involved in hepatocarcinogenesis remains controversial, but LC may progress HCC in heavy drinkers even if their serum markers for HBV (including tissue) or HCV are negative. Therefore, close observation, including radiographic examinations, is recommended for non-B, non-C, heavy drinkers with LC. In HCV-positive cases, abstinence or a reduction in daily ethanol intake is recommended.