Current protocols for prophylaxis against allograft reinfection after liver transplantation for chronic hepatitis B virus (HBV) infection include the administration of large doses of hepatitis B immune globulin (HBIG), with considerable associated economic costs. Monotherapeutic prophylaxis with lamivudine has been complicated by the development of resistant strains of HBV. We studied the effectiveness of a posttransplantation prophylaxis protocol using combination lamivudine and low-dose HBIG in 7 consecutive patients with chronic HBV infection, 4 of whom were serum HBV DNA positive before pretransplantation lamivudine therapy. All patients were serum HBV DNA negative at transplantation and received lamivudine, 100 mg/d, posttransplantation. HBIG, 2170 IU, was administered intramuscularly intraoperatively and daily for 14 days. Maintenance HBIG therapy consisted of 2170 IU intramuscularly twice weekly, tapered to every 2 to 4 weeks by 12 months posttransplantation. Target serum HBIG (HBV surface antibody) titers were less than 500 IU/L for 6 months, then greater than 300 IU/L until 12 months posttransplantation. Induction serum HBIG titers were determined daily in 5 patients, and both serum HBIG and hepatitis B surface antigen were determined every 4 weeks in all patients. One patient died 61 days posttransplantation; the surviving patients (n = 6) were followed up for a mean of 532 days (range, 395 to 648 days). No patient has developed allograft reinfection. In the induction period, a target HBIG titer of greater than 500 IU/L was not achieved until a mean of 6.8 days (range, 5 to 10 days). In the maintenance period, all patients achieved the target HBIG titer. This suggests combination lamivudine and low-dose HBIG is effective in preventing allograft reinfection by HBV.