Background & Aims: Hepatic fibrosis due to chronic HBV infection has enormous socioeconomic impact. Besides strategies targeting virus elimination, prevention or reversal of liver fibrosis is amenable. Given the antifibrotic activity of interferon-gamma (IFN-gamma), a randomized open-labeled multicenter trial was initiated to test IFN-gamma in HBV infection. Methods: HBsAg-positive patients with biopsy proven hepatic fibrosis (n = 99, stages 2-4, Scheuer criterion) were treated with diammone-glycyrrhizinate and potassium-magnesium aspartate. Sixty-six randomly assigned patients were treated with 50 jig IFN-gamma intramuscularly on a daily basis for 3 months and on alternate days the subsequent 6 months. Efficacy was evaluated by liver biopsy and serologic markers. Results: Fifty-four patients in the IFN-gamma group and 29 patients in the control group completed the study. The hepatic fibrosis score was significantly reduced in 63% of IFN-gamma treated patients compared with 24.1% in the control group by using a semiquantitative scoring system evaluating both liver architecture and fibrotic deposits. Mean values for the total fibrosis score decreased from 13.8 +/- 5.8 to 10.1 +/- 5.1 in the IFN-gamma group (P =.0001), whereas they were unchanged in control subjects (13.2 +/- 6.8 vs 12.6 +/- 4.8, P =.937). The Scheuer system showed 12 out of 54 patients improved >= 1 stage(s) in the IFN-gamma group compared with 1 of 29 in the control group. Antifibrotic activity might be attributed to decreased transforming growth factor-beta signaling via phosphorylated Smad2 and reduced number of activated, alpha-smooth muscle actin positive hepatic stellate cells. Conclusions: IFN-gamma treatment for 9 months improves fibrosis scores in patients with chronic HBV infection most likely by antagonizing profibrogenic transforming growth factor-beta effects.