No study has reported on the comparative effect of adefovir (ADV) add-on lamivudine (LAM) versus switching to entecavir (ETV) in LAM-resistant patients with chronic hepatitis B. From October 2007 to September 2008, 92 consecutive LAM-resistant patients were enrolled (47 LAM + ADV and 45 ETV 1 mg). All patients were followed for at least 12 months. The parameters assessed included normalization of ALT, HBeAg seroconversion, undetectable HBV DNA, reduction of HBV DNA, and predictors of virologic response. In the LAM + ADV and ETV groups, the baseline DNA levels were 7.61 (5.19–9.49) and 7.10 (5.43–9.74) log10 copies/ml, respectively. At month 12, a virologic response occurred in 18/47 (38.3%) and 11/45 (24.4%; P = 0.182) patients; ALT normalization, in 39/41 (95.1%) and 36/40 (90.0%; P = 0.432); HBeAg seroconversion, in 5.1% and 2.4% (P = 0.606); and virologic breakthrough, in 2.1% and 11.1% (P = 0.107), respectively. The mean reduction from the baseline HBV DNA level was greater in the LAM + ADV group at month 12 (3.80 ± 1.12 vs. 2.72 ± 1.32 log10 copies/ml; P < 0.001). In the multivariate analysis, the independent parameters related to a virologic response at month 12 were baseline ALT (OR = 1.003, 95% CI = 1.000–1.006, P = 0.026) and baseline HBV DNA (OR = 0.495, 95% CI = 0.298–0.823, P = 0.007). Compared with switching to ETV monotherapy, ADV add-on LAM therapy was more effective at reducing the viral load in patients with LAM resistance, and the baseline HBV DNA and ALT levels were independent predictors of the virologic response. However, ADV add-on therapy had limitations in patients with a higher baseline HBV DNA in LAM rescue therapy. J. Med. Virol. 82:1835–1842, 2010. © 2010 Wiley-Liss, Inc.