Background/Aims: This study evaluated the prevention by lamivudine of hepatocellular carcinoma (HCC) in chronic hepatitis B patients. Methods: Lamivudine therapy was administered to 879 of the 2,511 patients who satisfied our analysis inclusion criteria. A Cox regression model revealed that four factors increased the prevalence of HCC: gender (females; OR=0.53, p=0.006), age (≥40 years; OR=4.64, p ＜0.001), platelet count (≥100×10(3)/mm3; OR=0.35, p ＜0.001), and alcohol consumption (≥80 g/day; OR= 1.79, p=0.004). Five hundred and eighty-nine patients in the lamivudine-treated group and 589 patients in the control group were selected for a matched case-control study. The mean follow-up periods were 2.8 and 5.1 years in the lamivudine-treated and control groups, respectively. Results: HCC occurred in 10 patients (1.7%) of the lamivudine group, with an incidence rate of 0.61% patients/year, and in 65 patients (11.0%) of the control group, with an incidence rate of 2.16% patients/year. The cumulative incidence of HCC was lower in the lamivudine group than in the control group (p=0.0117, log-rank test). Conclusions: Lamivudine can reduce the incidence of HCC in patients suffering from chronic hepatitis B. (Gut and Liver 2007;1:151-158)