Primary tumor growth and metastasis depend on angiogenesis, which is determined by the balance between proangiogenic and antiangiogenic molecules. Interferon (IFN)-alpha and -beta inhibit angiogenesis through downregulation of interleukin-8, matrix metalloproteinase-9, and basic fibroblast growth factor. To provide evidence for the causal role of IFN-alpha/beta in the induction of neoplasms, their angiogenesis, and hence, progressive growth, we carried out experiments using 129S6 IFN-alpha/beta receptor -/- mice back-crossed to BALB/c nude mice. Subcutaneous angiogenesis was determined following implantation of gelfoam sponges containing 0.4% agarose and several proangiogenic molecules. Tumorigenicity and production of lung metastasis were determined subsequent to subcutaneous and intravenous injections, respectively, of highly metastatic A375SM human melanoma cells. Carcinogenesis was induced by chronic exposure of mice to UVB radiation (5 kJ/m2, 3 times/week). Angiogenesis, tumorigenicity, and production of metastasis, as well as development of autochthonous skin tumors, were all accelerated in IFN-alpha/beta receptor -/- mice as compared to control mice. Collectively, the data show that inability to respond to endogenous IFN-alpha/beta (through a mutation in the IFN-alpha/beta receptor) leads to increased susceptibility to carcinogenesis, enhanced angiogenesis, tumorigenicity, and metastasis.