Recent studies have revealed that both interferon (IFN) and angiotensin-converting enzyme inhibitor (ACE-I) exert an anti-fibrotic effect. The aim of this study was to examine the combined effect of the ACE-I and IFN on the murine hepatic fibrosis development. A model of CCl(4)-induced hepatic fibrosis was used to assess the effect of the clinically used ACE-I, perindopril (PE), and IFN-beta. The PE and IFN were administered after 2-week treatment with CCl(4), and the hepatic indices of fibrosis were assessed at 8 weeks. Single treatment with either PE or IFN at the clinically available comparable doses significantly attenuated liver fibrogenesis associated with suppression of the hepatic hydroxyproline and serum fibrosis markers. The number of alpha-smooth muscle actin-positive cells, and the hepatic alpha1(I)-procollagen mRNA were also markedly inhibited. The inhibitory effect of PE was more potent than IFN, and the combination treatment with PE and IFN almost completely attenuated liver fibrosis development. In vitro, the angiotensin-II (AT-II) type 1 receptor blocker and IFN suppressed the AT-II-induced proliferation and alpha1(I)-procollagen mRNA expression of the activated hepatic stellate cells. The combination treatment of the clinically used PE and IFN may provide a new strategy for anti-liver fibrosis therapy.