YMDD hepatitis B virus (HBV) mutants emerge in more than one third of patients treated with lamivudine. The development of escape mutants potentially limits the efficacy of this new therapy for chronic HBV infection. Transplant centers may be hesitant to perform orthotopic liver transplantation (OLT) in patients with progressive liver disease who develop the YMDD mutant because of concerns of graft reinfection. We describe a 56-year-old man with chronic liver disease caused by HBV who successfully underwent OLT after the emergence of a YMDD mutant and progressive liver disease. Perioperatively, he received high-dose intravenous hepatitis B immune globulin (HBIG) treatment with continued lamivudine treatment. Thirty-two months after OLT, there was no evidence of HBV reinfection with the use of lamivudine and high-dose HBIG. Our experience suggests that the emergence of a YMDD HBV mutant is not a contraindication to OLT. The combination of lamivudine and high-dose HBIG can protect against reinfection of the hepatic allograft with the YMDD HBV escape mutant.