A double case control study evaluated the role of hepatitis C virus (HCV) and hepatitis B virus (HBV), alcohol drinking, and tobacco smoking as potential risk factors for cepatocellular carcinoma (HCC). Fifty-one patients with HCC, 34 of whom had underlying cirrhosis, were analyzed against 51 hospital controls and 34 patients with cirrhosis, respectively. Sera from patients of all three groups were tested for HBV markers and anti-HCV antibodies. The polymerase chain reaction technique was used to detect HCV RNA in the anti-HCV-positive samples. Alcohol drinking and smoking habits were recorded for all patients. HCC risk was significantly related to the presence of hepatitis B surface antigen (HBsAg) [relative risk (RR) = 18], HCV infection (RR = 8), and alcohol abuse (RR = 4). When the presence of cirrhosis was taken into account, only HBsAg positivity was significantly associated with HCC development (RR = 6.7), indicating that HCV infection and alcohol abuse are related to HCC indirectly through the cirrhotic process. No significant interaction between HCV and HBV infection in the causation of HCC was found. Through the computation of population-attributable risk, it was found that 46% of the HCC cases in Greece could be attributed to HBsAg positivity but only 4% to HCV infection. In conclusion, HBV infection is the major risk factor in the development of HCC in Greece, either by inducing cirrhosis or by direct oncogenic effect. HCV infection is also related to HCC development, albeit indirectly through the cirrhotic process.