Hepatitis B virus (HBV) recurrence rates of 0-16% had been reported in patients maintained on nucleoside analogues (NA) after hepatitis B immunoglobulin (HBIG) discontinuation after orthotopic liver transplantation (OLT). However, follow-up in most studies was short. We aimed to determine the long-term risk of HBV recurrence using this strategy. All HBV patients who received Ն7 doses of intravenous HBIG after OLT, with no HBV recurrence while receiving HBIG, and who eventually discontinued HBIG and were maintained on NA, were included. HBV recurrence was defined as HBsAg-positive or HBV DNA Ն5 log copies/mL on 2 consecutive occasions. Twenty-one patients met the inclusion criteria. Immediate post-OLT prophylaxis was combination HBIG and NA in 15 patients, whereas 6 patients received HBIG monotherapy for 62-109 months before NA was added. HBIG was discontinued a median of 26 (range, 0.2-121) months after OLT. Median follow-up post-HBIG discontinuation was 40 (range, 5-51) months. Only 1 patient, who had 12 months of HBIG and was noncompliant to NA therapy, had HBV recurrence, 34 months after HBIG discontinuation. One patient had HBV DNA of 3.3 log copies/mL 47 and 48 months after HBIG discontinuation but remained HBsAg-negative. Lamivudine-resistant mutations were detected in both patients. Probability of HBV recurrence was 0% and 9% at 2 and 4 years after HBIG discontinuation. Three patients had 1-2 episodes of transiently detectable HBV DNA. All were HBV DNA and HBsAg negative on repeated tests over a period of 2-36 months. Maintenance therapy with NA after discontinuation of long-term HBIG therapy is associated with a low risk of HBV recurrence after OLT in compliant HBV patients. Liver Transpl 13: [374][375][376][377][378][379][380][381] 2007. © 2007 AASLD.Received June 29, 2006; accepted October 18, 2006. Before the advent of antiviral prophylaxis, the prognosis of patients undergoing orthotopic liver transplantation (OLT) for hepatitis B virus (HBV)-related liver disease was poor because of the high (80-100%) rate of graft reinfection after OLT.1,2 Recurrence of hepatitis B in liver transplant recipients generally follows a more aggressive course than in immunocompetent patients, with a 2-year mortality of 50%. Fortunately, tremendous strides in antiviral prophylactic measures have been made in the last 20 years. 3 The administration of either high-dose intravenous (IV) hepatitis B immunoglobulin (HBIG) or lamivudine (LAM) for an indefinite duration after OLT have resulted in a marked reduction in 3-year HBV recurrence rates to 15-25% for HBIG [4][5][6] and 20-40% for LAM monotherapy. [7][8][9] In recent years, the combination of IV HBIG and LAM resulted in further reduction in HBV recurrence rates to less than 10% up to 3 years after OLT. 6,[10][11][12][13]