Background: Telbivudine showed greater antiviral suppression than lamivudine in phase II and III clinical trials. Aims: The present phase IIIb, randomized, double-blind, multicentre global trial assessed the antiviral efficacy and safety of telbivudine switch in chronic hepatitis B (CHB) patients who exhibited persistent viraemia under lamivudine therapy. Methods: HBeAg-positive and HBeAg-negative adult patients (N = 246) with persistent viraemia [hepatitis B virus (HBV) DNA>3 log(10) copies/ml] under lamivudine treatment for 12-52 weeks were randomized (1: 1) to continue lamivudine 100 mg/day or switch to telbivudine 600 mg/day for 1 year. Primary endpoint was the reduction in serum HBV DNA levels from baseline at Week 24. Results: The mean reduction in serum HBV DNA levels from baseline with telbivudine was significantly higher than lamivudine at Week 24 (-1.9 +/- 0.18 vs. -0.9 +/- 0.27 log(10) copies/ml; P<0.001) and maintained through 1 year. The rate of treatment failure was significantly lower (P<0.001) for patients who switched to telbivudine (5%) compared with those who continued lamivudine (20%) after 52 weeks of treatment. In the telbivudine group, treatment failure occurred in only five patients with >24 weeks of prior lamivudine treatment, all associated with pre-existent lamivudine-resistant mutations. Genotypic resistance rates were higher in patients continuing lamivudine compared with those who switched to telbivudine with <24 weeks of lamivudine exposure. Both treatments were well tolerated with similar safety profiles. Conclusions: Early (<= 24 weeks) switch to telbivudine improves virological outcomes in CHB patients with persistent viral replication under lamivudine treatment.