Telbivudine (LdT) has demonstrated potent antiviral activity in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B patients (CHB), but data on its efficacy in NA-experienced patients are limited. The aim of this study was to investigate the effect of LdT in hepatitis B e antigen-positive CHB patients with poor response to initial adefovir dipivoxil (ADV). Forty-two CHB patients with HBV DNA > 4 log10 copies/mL after 12 months of ADV monotherapy were enroled in the study and thereafter treated with LdT 600 mg daily for 18 months. Telbivudine led to a rapid decrease in viral load, and viral replication was persistently suppressed with a reduction of 2.26 log10 copies/mL 18 months after LdT treatment. The rates corresponding to virological and biochemical response at the end of observation were 97.6% (41/42) and 65.8% (25/38), respectively. HBeAg loss was found in 30.8% (12/39) of patients, while HBeAg/anti-HBe seroconversion was found in 17.9% (7/39). Only one patient was detected to have LdT-associated mutation, and no severe adverse events were reported. Optimization therapy with LdT monotherapy may be a good choice for CHB patients with poor response to ADV, and switching to LdT may be the most cost-effective rescue therapeutic strategy for patients with poor response to initial ADV monotherapy.