Summary. Adefovir dipivoxil is effective against lamivudine-resistant hepatitis B virus (HBV) strains. Whether short-term overlap lamivudine is beneficial remains unknown, particularly in patients with decompensated chronic hepatitis B. We enrolled 30 patients who underwent 48-week adefovir treatment (10 mg daily) for exacerbation of hepatitis B, associated with lamivudine-resistant mutants. Nineteen (63.3%) patients had baseline evidence of hepatic decompensation. Lamivudine was combined for ≤1 month in eight (group I), 2–5 months in 10 (group II) and ≥6 months in 12 (group III). We analysed their serial alanine aninotransferase (ALT) levels, Child–Pugh (CP) score, serum viral load and lamivudine-resistant strains. We found that serum ALT became normalized in 20 (66.7%) and HBV-DNA decreased to ≤100 copies/mL in eight (26.7%) at the end of the 48-week treatment. The log(10) reduction of serum HBV-DNA was significantly smaller in group I patients compared with group II and III patients at week 24 and 48 of treatment [median (range): 3.0 (1.5–5.6) vs 4.5 (1.5–7.4), P = 0.032; and 3.4 (0.9–4.7) vs 5.2 (2.2–7.7), P = 0.008 respectively]. In contrast, the virologic responses at the end of the 48-week therapy were similar between group II and III patients. The improvement in serum ALT and CP score at week 48 was similar irrespective of baseline decompensation, liver cirrhosis and the duration of overlap lamivudine therapy. Our findings suggested that an overlap of lamivudine for ≥2 months might lead to better virological but not biochemical outcomes in patients receiving adefovir for lamivudine-resistance HBV. As our sample size was small and the study was not randomly controlled, further studies are needed.