AIM: To observe the efficiency and safety of thymosin-α1treatment in patients with hepatitis B e antigen (HBeAg)and HBV DNA positive chronic hepatitis.METHODS: Sixty-two patients were randomly divided into groups A and B. The patients in group A received subcutaneous injection of 1.6 mg thymosin-α1, twice a week (T-α1 group) for six months, and the patients in group B received 5 MU interferon alpha (IFN-α) each day for fifteen days, then three times weekly (IFN-α group)for six months. The results between two groups treated with and the group untreated with IFN-α which was followed up for 12 mo (historical control group consisting of 30 patients) were compared, and three groups were comparable between each other (P ＞ 0.05) at baseline (age, sex, clinical history, biochemical, and serological parameters).RESULTS: At the end of treatment, complete response,which was defined as alanine aminotransferase (ALT)normalization and HBV DNA and HBeAg loss, occurred in 9 of 29 (31.0%) patients in the T-α1 group and in 15 of 33 (45.5%) patients in the IFN-α group (x2= 1.36, P ＞0.05). After a follow-up period of six months, a complete response was observed in 14 of 29 (48.3%) patients in the T-α1 group and in 9 of 33 (27.3%) patients in the IFN-α group (x2= 2.93, P ＞ 0.05). Compared with the results observed in the historical control (HC) group untreated with IFN-α which was followed up for 12 mo,the rate of complete response was significantly higher in IFN-α group at the end of therapy (1 of 30 vs 15 of 33,x2 = 14.72, P ＜ 0.001) and in the T-α1 group at the end of follow-up (1 of 30 vs 14 of 29, x2 = 15.71, P ＜ 0.001).In T-α1 and IFN-α treatment groups, the area under (the plasma concentration time) curve (AUC) of negative HBV DNA and HBeAg was 34%, 17%, 31% and 19% smaller than that in the HC group. By the end of the followup period, the proportions of ALT normalization and negative HBV DNA in the T-α1 group were significantly higher than those in the IFN-α and HC groups. The odds of ALT normalization and negative HBV DNA at the end of the follow-up was three-fold higher in the T-α1 group than in the IFN-α group. Unlike IFN-α, T-α1 was well tolerated by all patients, and no side effects appeared in T-α1 group.CONCLUSION: The results suggest that a 6-mo course of T-α1 therapy is effective and safe in patients with chronic hepatitis B. T-α1 is able to reduce HBV replication in patients with chronic hepatitis B. Furthermore, T-α1is better tolerated than IFN-α and can gradually induce more sustained ALT normalization and HBV DNA and HBeAg loss. However, a response rate of 48.3% is still less ideal. A more effective therapeutic approach warrants further study.