At present, there is no consensus treatment for patients who have poor response to Adevofir dipivoxil (ADV) monotherapy and no ADV-associated mutation. The purpose of this study was to evaluate the effect of a new therapeutic strategy combining Lamivudine (LAM) and ADV in patients with HBeAg-positive chronic hepatitis B (CHB) and poor response to ADV monotherapy. Thirty-one patients with chronic hepatitis B with HBV DNA > or = 10(4) copies/mL after 48 weeks of ADV monotherapy were included and received ADV plus LAM for 24 weeks. Compared with ADV monotherapy, ADV + LAM had an improved response rate at weeks 12 and 24 - compared with baseline, the median decrease in HBV-DNA level at week 12 and 24 were 1.27 and 2.03 log respectively. The virological response (VR) rate (HBV-DNA level <10(3) copies/mL) was 6.5% and 35.5% at weeks 12 and 24, respectively; the biochemical response (BR) rate (normalization of alanine aminotransferase levels) was 67.8% and 100%, respectively; the HBeAg loss rate was 6.9% and 34.5%, respectively; and the seroconversion rate (from HBeAg to HBeAb) was 3.5% and 6.9% respectively. No ADV-associated mutation was detected at baseline. After combination therapy for 24 weeks, no LAM-resistant or ADV-resistant mutations were detected. Only one patient had a mild adverse reaction. In conclusion, optimization of therapy combining LAM and ADV may be a good choice for patients with hepatitis B who have a poor response to ADV monotherapy.