Treatment of chronic hepatitis B (CHB) is difficult. The response rate to interferon (IFN) as well as nucleoside analogs is not more than 30% in general. While interferon has many side effects, development of resistance in most of the nucleoside analogs precludes long-term use. Both groups of drugs are most efficacious in patients who already had or develop strong cellular immunity with treatment. A pre-S2-containing vaccine was shown to enhance cellular immunity and suppress hepatitis B virus (HBV)-DNA in subjects with chronic hepatitis B. We aimed to test the efficacy of short-term use of a nucleoside analog in combination with a pre-S2-containing vaccine in patients with CHB. In this open study, 48 consecutive patients (32 males and 16 females, mean age +/- A SD: 33 +/- A 12 years) with CHB without cirrhosis were treated with 100 mg/day lamivudine and four weekly intramuscular injections of Genhevac B 20 mcg (six doses) for 24 weeks. While 19 patients were hepatitis B e antigen (HBeAg) positive (+ve), 29 patients were Anti-HBe/HBV-DNA +ve at the outset. Response was defined as seroconversion to anti-HBe in HBeAg +ve subjects and normalization of alanine aminotransferase (ALT) with loss of HBV-DNA in anti-HBe/HBV-DNA +ve subjects. HBeAg seroconversion occurred in 5/19 subjects (26%). Eighteen of 29 anti-HBe/HBV-DNA +ves responded. In the follow-up, while relapse was not observed in any of the patients who seroconverted, 11/18 from the anti-HBe/HBV-DNA +ve group relapsed, resulting in a sustained response (SR) rate of 24% in this group. All the relapses happened in the first 48 weeks of follow-up, with no relapse thereafter. Pretreatment high serum HBV-DNA was a strong negative predictor of sustained response (SR) in HBeAg +ve group. Pretreatment serum ALT over 2 x upper limit of normal and HBV-DNA less than 200 pg/ml appeared positive predictors. None of HBeAg +ve previous interferon failures responded. Twenty-four weeks of lamivudine and hepatitis B vaccine treatment induces SR in around 1/4 of the patients with CHB. Most of the responders had high ALT and relatively low DNA.