Abstract： Objective To investigate the risk factors of hepatitis B virus(HBV) re-infection after orthotopic liver transplantation(OLT)and to evaluate the therapeutic efficacy of hepatitis B immunoglobulin(HBIG)combined with nucleos(t)ide analogues. Methods The study included 160 patients with HBVrelated liver diseases who underwent OLT in the Third Affiliated Hospital of Sun Yat-sen University from October 2003 to Augest 2007, 117 of whom were treated with nucleos(t)ide analogues before OLT;and all patients were received HBIG i. m and nucleos(t)ide analogues treatment after OLT. Preoperative data of the patients were retrospectively reviewed, and HBV re-infection was assessed prospectively. Independent t test was used to compare normally distributed data and Fisher's exact test was used for the comparison of rates among groups. Results HBV re-infection Was observed in 19 patients after OLT with a rate of 11. 88%(19/160), which was not correlated with HBV DNA loads, HBeAg and the duration of antiviral therapy before OLT(r=0.108, 0.127 and 0.033, P>0.05). Of 19 patients with HBV re-infection, 17 were treated with lamivudine after OLT, and HBV YMDD mutants were detected in 8. The YMDD positive group had a higher HBV DNA level than YMDD negative group(7.0 ± 2.0 log copies/mL vs 3.2 ± 2.5 log copies/mL, t = 3.531, P=0.003). Among above 17 patients, 12 received adefovir add-on treatment, and3 received entecavir instead of lamivadine; all achieved satisfactory responses. Conclusions Low dose of HBIG combined with long-term use of nucleos(t)ide analogues can effectively prevent HBV re-infection after OLT. HBV YMDD mutation may be the primary reason for HBV re-infection in the patients treated with lamivudine after OLT.