Lamivudine (LMV) treatment in patients with hepatitis B virus (HBV) infection may improve clinical state and suppress viral replication. Emergence of LMV-resistant YMDD mutant is a common and challenging complication. This study assesses the safety, biochemical and virological responses to Adefovir (ADV;10 mg daily) therapy in these patients. Forty-two consecutive patients were treated with ADV due to emergence of LMV-resistant YMDD mutant strain (n=38), poor response (n=3), and development of severe acute pancreatitis (n=1) were included. Thirty-seven (88.1%) were males, 12 (28.6%) were post-liver transplantation, and 19 (45.2%) were HBeAg negative. The mean±SD age and body weight were 43.4±16.4 years and 69.5±19.8 kilograms respectively. Concomitant HCV or HDV infections existed in 4 (9.5%) cases and 11 (26.2%) were diabetic. The median (range; mean±SD) duration of LMV therapy and the follow up period on ADV therapy were 34 (4-66; 32±15.9) and 16.9 (1.03-33.0; 16.8±7.8) months respectively. Full biochemical response (transaminases normalization), partial virological (one Log reduction), and full virological (complete viral clearance) responses were observed in 27 (64.3%), 6 (14.3%), and 16 (38.1%) patients respectively. The response to ADV therapy was significantly higher in HBeAg negative patients than in HBeAg positive ones (15 out of 19; 78.0% and 7 out of 23; 30.4% respectively; p=0.002). Also, the response to ADV tends to be more in post-liver transplantation patients (9 out of 12; 75.0%) than pre-transplant cases (13 out of 30; 43.3%) although it did not reach statistical significance (p=0.09). No adverse effects were encountered any patient during the whole follow up period. ADV is a safe and effective therapy in patients with pre- and post- transplantation YMDD actively replicating HBV mutant. The response to ADV is more in HBe Ag negative cases, and appears to be better in post-liver transplant cases.