A population-based case-control study was carried out to investigate risk factors for hepatocellular carcinoma (HCC) in Nagoya, Japan, including hepatitis virus infections, drinking and smoking habits and genetic polymorphisms in aldehyde dehydrogenase2 (ALDH2) and cytochrome P4502E1 (CYP2E1). A total of 84 patients with HCC and 84 sex, age and residence pair-matched controls were recruited for this study. By univariate analysis, hepatitis B virus (HBV) (OR=5.14; 95%CI=2.29-11.6) and hepatitis C virus (HCV)(OR=32.00; 95%CI=7.83-130.7) infections, having a history of blood transfusion (OR=5.25; 95%CI=1.80-15.29), and habitual smoking (OR=2.36; 95%CI=1.17-4.78) were significantly linked to cases; by multivariate analysis, HCV infection (OR=23.5; 95%CI=5.07-108.9) and habitual smoking (OR=5.41; 95%CI=1.10-26.70) were still associated with a significantly increased risk. The c1/c1 genotype of CYP2E1 (odds ratio [OR]= 0.45; 95% confidence interval [CI]=0.21-0.99), detected by Pstl and Rsal digestion was significantly more prevalent in the control group, while 1-1 genotype of ALDH2 (OR=1.24; 95%CI=0.70-2.20) did not demonstrate variation. There were no statistically significant interactions between habitual smoking/drinking and genetic polymorphisms of ALDH2/P4502E1 with reference to HCC development. These findings suggest that viruses, especially HCV infection, and habitual smoking are major independent risk factors, while genetic polymorphisms of ALDH2 and CYP2E1 have only limited contribution to the risk of HCC in Nagoya, Japan.