Pulmonary hypertension (PH) is a progressive and fatal disease with no cure. Vascular remodeling in PH involves intraluminal growth of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Cell growth in these lesions is quasi-neoplastic, with evidence of monoclonality, apoptosis resistance and cancer-like metabolic derangements. Herein we tested the effect of human interferon alpha 2b (IFNa), a pleiotropic cytokine and anti-cancer therapeutic, on the development and progression of PH in the rat SU5416/hypoxia (SUH) model and mouse hypoxia model of the disease. In both models IFNa attenuated the development of PH and reversed established PH as assessed by measuring right ventricular systolic pressure and right ventricular hypertrophy. The effect of IFNa was dependent on the type I interferon receptor (IFNAR) since mice lacking a subunit of the IFNAR were not protected by IFNa. Morphometric analysis of pulmonary aterioles from hypoxic mice or SUH rats showed that IFNa inhibited pulmonary vascular remodeling in both models and that IFNa reversed remodeling in SUH rats with established disease. Immunohistochemical staining revealed that IFNa decreased the number of PCNA and Tunel positive cells in the wall of pulmonary arterioles. In vitro, IFNa inhibited proliferation of human pulmonary artery smooth muscle cells and as well as human pulmonary artery endothelial cell proliferation and apoptosis. Together these findings demonstrate that IFNa reverses established experimental PH and provide a rationale for further exploration of the use of IFNa and other immunotherpies in PH.