Lamivudine monoprophylaxis against hepatitis B virus (HBV) reinfection after liver transplantation is associated with recurrence due to escape mutants and second generation recombinant HBV vaccine is not effective. We studied the efficacy of two courses each of three double-doses (20 microg) of third-generation recombinant pre-S containing vaccine (Sci-B-Vac) in 20 patients on lamivudine prophylaxis at a median of 637 days (range, 390-2666 days) after transplantation. At enrollment, all patients were seronegative for HBsAg, anti-HBs and HBVDNA (by qPCR). Lamivudine (100 mg/day) was continued throughout the study. Five patients (25%) responded to the first course and five additional patients responded after the second course (overall response rate 50%). The response rate was 88% in patients younger than 50 years old and 25% in older patients (p = 0.02). The median peak anti-HBs titer was 153 mIU/mL with six responders having a titer >100 mIU/mL and seven sustained >6 months. Among seven previous nonresponders to second generation recombinant vaccine, three (44%) responded. At the end of the study, all patients remained seronegative for HBsAg. In conclusion, Sci-B-Vac is effective in about 50% of patients receiving lamividine prophylaxis and may prevent recurrence due to escape mutants.