Adefovir dipivoxil (ADV) has demonstrated clinical activity against both wild-type and lamivudine-resistant hepatitis B virus (HBV). We analyzed the evolution of viral load and the changes of polymerase and precore/core promoter sequences in lamivudine-resistant virus during ADV therapy. The authors studied 14 patients who had breakthrough hepatitis after lamivudine therapy. Serial sera were obtained prior to adefovir administration and at 3, 6 and 12 months after ADV therapy. Nucleotide sequences of polymerase and the precore/core promoter from the hepatitis B virus were analyzed. The median serum HBV DNA decrease with adefovir treatment was 4.35 log10 copies/mL at 12 months. Tyrosine-methionine-aspartate-aspartate (YMDD) mutants were found in 12 patients among the 14 patients with lamivudine resistance. The YMDD mutant viruses reversed to the wild-type in 6 patients out of the 12 patients after 3–6 months of ADV after discontinuing lamivudine therapy. In the analysis of the nucleotide sequences of the precore/core promoter gene, core promoter mutants in 12 patients were replaced by wild-type virus in three patients (25%), while precore mutants in four patients were replaced by the wild-type in three patients (75%). The results demonstrate the patterns of polymerase and precore/core promoter mutations in lamivudine-resistant hepatitis B viruses and the reversion from the mutant to the wild-type in some patients. In addition, despite several mutations in the polymerase during ADV therapy, ADV effectively suppressed HBV replication without the emergence of resistant viral mutants. J. Med. Virol. 79:902–910, 2007. © 2007 Wiley-Liss, Inc.