Background In this study, we aimed to identify baseline predictors of response in chronic hepatitis B patients treated with a combination of pegylated interferon (PEG-IFN)-α2a and adefovir. Methods We treated 92 chronic hepatitis B patients (44 hepatitis B e antigen [HBeAg]-positive and 48 HBeAg-negative) with HBV DNA>100,000 copies/ml (>17,182 IU/ ml) with PEG-IFN and adefovir for 48 weeks and followed them up for 2 years. Baseline markers for HBeAg loss, combined response (HBeAg negativity, HBV DNA levels ≤2,000 IU/ml and alanine aminotransferase [ALT] normalization) and hepatitis B surface antigen (HBsAg) loss were evaluated. Results Two years after the end of treatment, rates of HBeAg loss and HBsAg loss in HBeAg-positive patients were 18/44 (41%) and 5/44 (11%), respectively. In HBeAg-negative patients, rates of combined response and HBsAg loss were 12/48 (25%) and 8/48 (17%), respectively. HBeAg-negative patients with HBsAg loss had lower baseline HBsAg levels than those without HBsAg loss (mean HBsAg 2.35 versus 3.55 log 10 IU/ml; P<0.001). They also had lower HBV DNA levels and were more often (PEG-)IFN experienced. Baseline HBsAg was the only independent predictor of HBsAg loss (OR 0.02; P=0.01). Conclusions With combination therapy of PEG-IFN and adefovir for 48 weeks, a high rate of HBsAg loss was observed in both HBeAg-positive (11%) and HBeAg-negative (17%) patients 2 years after treatment ended. In HBeAg-negative patients, a low baseline HBsAg level was a strong predictor for HBsAg loss.