Abstract: Objective To evaluate the therapeutic effects of entecavir (ETV) and interferon-α (IFN-α) treatments for 48 weeks for chronic hepatitis B (CHB) in patients with different baseline alanine aminotransferase (ALT) levels. Methods We retrospectively analyzed the data of 369 CHB patients receiving ETV and IFN-α treatments for 48 weeks. We compared the virological response rates, HBsAg clearance, and HBsAg reduction between the patients receiving ETV and IFN-α treatments with different baseline ALT levels [≤5×upper limits of normal (ULN) level (subgroup 1), 5-10×ULN (subgroup 2), and >10× ULN (subgroup 3)]. Results In patients receiving ETV treatment, the virological response rate was 83.3% in subgroup 1, 91.4% in subgroup 2, and 95.5% in subgroup 3, as compared with 19.7%, 40%, and 42.9% in the 3 subgroups with IFN-α treatment, respectively, showing significantly differences both among different subgroups with the same treatment and between the same subgroup with different treatments (P<0.05). HBeAg clearance rates in the 3 subgroups were 8.3%, 16.7% and 35.5% in patients with ETV treatment and were 1.8%, 41.9%, and 38.1% in patients with IFN-α treatment, respectively, showing significant differences among the 3 subgroups with the same treatment (P<0.05); in the same subgroups with different treatments, the rates differed significantly only between subgroups 2 (P<0.05). In ETV group, the rate of HBsAg reduction to below 200 IU/ml was 2.5% in subgroup 1 and 13.8% in subgroup 2, showing no significant difference between the two subgroups; in IFN-α group, the rates were also similar between subgroups 1 and 2 (30.6% vs 33.3%, P>0.05); but the rates differed significantly between the same subgroups with different treatments (P<0.05). Conclusion In all the subgroups with different baseline ALT levels, ETV treatment for 48 weeks results in significantly higher virological response rates than IFN-α treatment in patients with CHB. In patients with a baseline ALT of 5-10 ×ULN, IFN-α can result in a higher HBeAg clearance rate than ETV. In patients with comparable baseline ALT level, IFN-α more effectively reduces HBsAg level than ETV. The patients with a relatively high baseline ALT level (>5 × ULN) show better responses to both ETV and IFN-α treatment than those with ALT level below 5×ULN. We thus recommend IFN-α for patients with a baseline ALT of 5-10×ULN and ETV for patients with a baseline ALT either below 5 × ULN or beyond 10×ULN.