Background Pegylated interferon (PEG-IFN)-α-2a improves the hepatitis B e antigen (HBeAg) seroconversion rate in HBeAg-positive chronic hepatitis B patients. However, baseline factors predicting favourable responses to PEG-IFN-α-2a remain largely unknown. Methods A total of 115 HBeAg-positive chronic hepatitis B patients who had a pre-therapy serum alanine amino-transferase (ALT) level over two times the upper limit of normal and received PEG-IFN-α-2a for 6–12 months were consecutively enrolled according to the local reimbursed guidelines. HBeAg seroconversion and combined response defined as HBeAg seroconversion, HBV-DNA level <20,000 IU/ml as well as ALT normalization at 6 months off therapy were primary and secondary therapeutic end points, respectively. Baseline viral factors, including viral load, genotype and major sequences of precore stop codon/ basal core promoter (BCP), and host factors, including three single nucleotide polymorphisms among the HLA-DPA1, HLA-DPB1 and IL28B regions, were determined to correlate with therapeutic end points. Results HBeAg seroconversion and combined response rates were 26.1% and 18.3%, respectively. By multivariate analysis, BCP mutation (OR 8.04, 95% CI 2.00-32.28) and rs3077 G/G genotype (OR 3.49, 95% CI 1.12-10.84) were associated with a higher HBeAg seroconversion rate; BCP mutation (OR 9.28, 95% CI 1.92-44.99) and baseline viral load <2x10⁶ IU/ml (OR 4.78, 95% CI 1.37-16.69) were associated with a higher combined response rate. Conclusions BCP mutation is associated with higher HBeAg seroconversion and combined response rates at 6 months off therapy in HBeAg-positive chronic hepatitis B patients treated with PEG-IFN-α-2a. Genetic variants in the HLA-DPA1 region may also affect treatment-induced HBeAg seroconversion.