Orthotopic liver transplantation (OLT) recipients without hepatitis B virus (HBV) infection who receive liver grafts from antibody to hepatitis B core antigen-positive [HBcAb(+)], hepatitis B surface antigen-negative [HBsAg(-)] donors have an increased risk of developing de novo hepatitis B infection. We compared the 2 most commonly employed prophylactic regimens-lamivudine (LAM) monotherapy and hepatitis B immunoglobulin (HBIG)+LAM combination therapy-to determine the relative efficacies of these 2 protocols in preventing de novo hepatitis B infection. A comprehensive search of the Cochrane Database of Systematic Reviews, MEDLINE (1966 to June 2009), and bibliographies of retrieved trials was conducted. Eligible studies included OLT recipients who received HBcAb(+) liver grafts and were treated prophylactically with either LAM monotherapy or HBIG+LAM combination therapy. 13 studies were identified as meeting the eligibility criteria. The rates of de novo hepatitis B infection, mortality, and mortality due to de novo hepatitis B infection were assessed. The incidence of de novo hepatitis B infection was 2.7% (n = 73) in patients receiving LAM-only prophylaxis versus 3.6% (n = 110) in patients receiving HBIG+LAM combination therapy. In the HBIG+LAM group, the dose and duration of HBIG therapy were highly variable. The median follow-up time for the LAM monotherapy group was 25.4 months with a range of 14.78 to 27.6 months, whereas the median follow-up time for the LAM+HBIG group was 31.1 months with a range of 15.3 to 38.5 months. The risk of developing de novo hepatitis B infection based on the pretransplant recipient HBV serology in each treatment group could not be calculated because of incomplete data and the limited number of de novo hepatitis B infection cases in the series reviewed. In conclusion, on the basis of these findings, we conclude that published studies have not shown HBIG+LAM combination therapy to be more effective than LAM-only treatment. Nucleoside analogue monotherapy should therefore be considered when one is treating HBV(-) patients who have received liver allografts from HBcAb(+) donors.