The best interferon-alfa (IFNα) regimen for HBeAg negative chronic hepatitis B has not been established yet. We evaluat-ed the efficacy of three regimens of IFNα in 75 patients with histologically documented HBeAg negative chronic hepati-tis B, who were randomly allocated to receive IFNα-2b thrice weekly in a dose of: 3MU for 12 months (Group A, n=25); 5 MU for 6 months and 3 MU for another 6 months (Group B, n=25); and 3 MU for 6 months and 1 MU for another 6 months (Group C, n=25). Initial biochemical response was observed in 71% of the 75 patients and initial virological re-sponse (undetectable serum HBV DNA by bDNA assay) in 38% of the patients with pre-treatment detectable serum HBV DNA. The decline of HBV DNA levels at the end of therapy was significant in group A (P=0.02) or B (P=0.004), but not in group C. Sustained biochemical and virological response rates (at 6 months after the end of therapy) were 35% and 22% respectively, without any significant difference among the three groups. There was a significant improvement in the grading (P<0.001) and no significant change in the staging of the post-treatment liver biopsies at 6 months after the end of therapy compared with the pre-treatment histological find-ings. In conclusion, a 12-month course of IFNα can induce sustained biochemical response in about one third and sus-tained virological response in approximately one fifth of pa-tients with HBeAg negative chronic hepatitis B. A standard dose of 3 MU IFNα thrice weekly seems to be the most cost effective therapeutic regimen.