Reactivation of chronic hepatitis B virus (HBV) infection is a major cause of morbidity and mortality after renal transplantation. Although lamivudine is an effective treatment for chronic hepatitis B, the development of drug resistance due to mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif is a major concern, especially in immunosuppressed patients who require prolonged therapy. Treatment with famciclovir has not been effective in the majority of patients who developed lamivudine resistance due to methionine-to-valine mutation at position 550, because this mutation has been uniformly associated with leucine-to-methionine mutation at position 526, a mutation that is associated with resistance to famciclovir. We describe a renal transplant recipient with an uncommon lamivudine-resistant HBV variant, in which methionine-to-valine/isoleucine mutation at position 550 was associated with wild-type sequence at position 526. The severe hepatitic flare consequent to the lamivudine resistance in this patient was successfully treated with famciclovir, indicating that both M550V and M550I mutants with preserved wild-type sequence at position 526 of HBV reverse transcriptase are susceptible to famciclovir. Our experience shows that famciclovir can be useful in selected patients with otherwise potentially fatal hepatitic flares related to lamivudine resistance, and that analysis of mutations in the HBV variant can be helpful in the choice of antiviral therapy.