A considerable proportion of liver transplantation recipients who receive hepatitis B immunoglobulin (HBIG) monotherapy for hepatitis B virus (HBV) prophylaxis develop resistance to HBIG. We retrospectively assessed the efficacy of HBV prophylaxis in 1524 patients who received primary high-dose HBIG monotherapy (n = 1463) or with a preemptive antiviral add-on as secondary combination therapy (n = 61). At a median follow-up time of 57 months, 106 (7.3%) patients receiving HBIG monotherapy experienced HBV recurrence, with a 10-year HBV recurrence rate of 9.8%, compared to none of the patients receiving preemptive combination therapy (P = 0.047). Thirteen patients (12.3%) with HBV recurrence failed antiviral therapy, leading to death or retransplantation. Response rates to rescue therapy before and after use of adefovir/entecavir were 44.4% and 91.8%, respectively. Acute exacerbation was not associated with treatment failure, but required prolonged treatment. Of 84 surviving patients with HBV recurrence, 44 (52.4%) showed no evidence of blood HBV DNA. The Gly145Arg mutation was found in 11 of 15 (73.3%) patients, whereas 25 of 71 (35.2%), 2 of 29 (6.9%), and 4 of 8 (50%) patients were resistant to lamivudine, adefovir, and entecavir, respectively. In conclusion, our finding of a 10-year HBV recurrence rate of 9.8% in patients receiving high-dose HBIG monotherapy indicates that this treatment is effective but requires complementary measures. Strict surveillance following HBIG monotherapy is necessary to enhance responses to rescue antiviral therapy. Preemptive conversion to combination therapy has a complementary role in prophylaxis with primary high-dose HBIG monotherapy, especially for patients at high risk of HBV recurrence. Liver Transpl, 2011. © 2011 AASLD.