Background: The main aim of the treatment of chronic hepatitis B is to suppress HBV replication before irreversible liver damage occurs. In this study we evaluated the short-term efficacy and safety of alpha-2b interferon (Heberon Alpha R) on Iranian patients with chronic HBV infection.Methods: From 2002 to 2003, in a multicentric uncontrolled trial, 68 patients with chronic hepatitis B (HBeAg+: 32.4% & HBeAg-: 67.6%) treated with Heberon Alpha R in the mean dose of 31.32± (SD) 7.3 MU/Wand in mean duration of 5.32±.95 month. The biochemical response (BR) was defined as decrease in serum ALT level to within the normal range, virologic response (VR) as loss of serum HBV DNA on PCR and loss of HBeAg in patients who were initially HBeAg-positive, and BR+VR as complete response (CR). Result: During the treatment with Hebron did not report any serious or unexpected adverse reaction in treated patients. At the end of treatment, with per-protocol analysis, BR, VR, and CR were 58.8%, 47.5%, and 44.1 %, respectively. Complete response was significantly associated with pretreatment high serum ALT levels (P=. 002), high pathological liver grades (P=. 001), and a higher dose/week of INF-α (P=.001).Conclusion: In this study we showed an acceptable safety and efficacy for Hebron (a preparation of alpha-2b interferon) in the treatment of Iranian patients with chronic hepatitis B. These results should be supported by well-conducted randomized, controlled trials and evaluation of its long-term effects on chronic hepatitis B infection.