The most effective means of preventing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is to prevent HBV infection via global vaccination of infants. Universal vaccination of newborns has been shown to significantly reduce the incidence of HCC among Taiwanese children. Among HBV carriers, the incidence of HCC was significantly higher in those who were hepatitis B e antigen positive, suggesting that antiviral therapy that results in viral clearance or sustained suppression of HBV replication should reduce the incidence of HCC. Review of data from >1000 chronic hepatitis B patients who received interferon treatment found that interferon has no or minimal overall effect on preventing HCC, but a beneficial effect may be attained in responders. The negative results are in part related to the small number of patients, short duration of follow-up, and low response rate to interferon therapy. Only 1 prospective randomized controlled trial of antiviral therapy with incidence of HCC as an endpoint has been reported. In this trial, 651 Asian patients with compensated HBV-related cirrhosis were randomized to receive lamivudine or placebo. After a median follow-up of 32 months, HCC was diagnosed in 3.9% lamivudine-treated patients and in 7.4% placebo controls ( P = 0.047). Further studies using antiviral agents with lower risk of drug-resistance are needed to confirm these results. In addition, questions on who to treat and how long treatment should be administered must be addressed before recommendations on the use of antiviral therapy to prevent HBV-related HCC can be made.