BACKGROUND. Prophylaxis to prevent recurrent HBV infection in liver transplant (LT) recipients has evolved over time, and we manage patients who receive lamivudine monoprophylaxis, lamivudine with HBV immunoglobulin (HBIg), and lamivudine and adefovir with HBIg. METHODS. Serum was examined with sensitive assays to detect the persistence of HBV, and to identify mutations that might confer resistance to the antiviral prophylaxis. Forty patients were studied, and sera were collected 20 days to 13.3 years after LT. RESULTS. Overall, HBV DNA was detected in serum of 67.5% of patients (8 of 10 of lamivudine monoprophylaxis patients, 15 of 24 of those receiving lamivudine and HBIg, and 4 of 6 of those receiving lamivudine, adefovir and HBIg). Thus, HBV infection persists for most of the patients despite successful prophylaxis after LT. Of those patients with detectable serum HBV DNA, three of eight of the lamivudine monoprophylaxis group had sequences associated with resistance to lamivudine (YMDD mutants), compared with only 1 of 15 of the lamivudine and HBIg cohort. Three of the lamivudine and HBIg cohort had the I126A Hepatitis B surface antigen escape variant. In those serum HBV DNA-positive patients who were receiving lamivudine, adefovir, and HBIg, only one of four had YMDD mutant, and none had Hepatitis B surface antigen escape variants. None of the 40 patients suffered clinical HBV recurrence. CONCLUSIONS. Our observations imply that the selection of resistant virus may be essential, but is not sufficient to cause overt failure of prophylaxis with development of clinical disease. It seems likely that the patients' immune response contributes, at least partially, to the long-term control of infection in these patients.