Angiogenesis is now recognized as playing a pivotal role in hepatocarcinogenesis. The aim of our current study was to examine the combination effect of the clinically used interferon-beta (IFN) and angiotensin-converting enzyme inhibitor, perindopril (PE), on hepatocarcinogenesis induced by diethylnitrosamine, especially in conjunction with angiogenesis. Single treatment with either IFN or PE significantly attenuated the development of hepatocellular carcinoma (HCC), and the combination of IFN and PE nearly abolished hepatocarcinogenesis. Both IFN and PE also significantly suppressed the neovascularization and expression of the vascular endothelial growth factor (VEGF), a potent angiogenic factor, in the tumor. These inhibitory effects were similar in magnitude to their inhibitory effects against hepatocarcinogenesis. The combined treatment with IFN and PE resulted in a marked increase of apoptosis in the tumor, whereas tumor cell proliferation was not altered. These results suggested that the combination treatment with IFN and PE may be an effective new strategy for chemoprevention against HCC.