RATIONALE: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by progressive vasoconstriction and obliterative vascular remodeling that leads to right heart failure (RHF) and death. Current therapies do not target vascular remodeling and RHF, and only result in modest improvement of morbidity and mortality. OBJECTIVE: To determine whether targeting HIF-2alpha with a HIF-2alpha-selective inhibitor could reverse PAH and RHF in different rodent PAH models. METHODS: HIF-2alpha and its downstream genes in lung samples and pulmonary arterial endothelial cells (PAECs) and smooth muscle cells (SMCs) from idiopathic PAH (IPAH) patients as well as different rodent PAH models. A HIF-2alpha selective inhibitor was used in human lung microvascular endothelial cells and in Egln1Tie2Cre mice, and Sugen 5416/hypoxia or monocrotaline-exposed rats. MEASUREMENT AND MAIN RESULTS: Upregulation of HIF-2alpha and its target genes were observed in lung tissues and isolated PAECs from IPAH patients and three distinct rodent PAH models. Pharmacological inhibition of HIF-2alpha by the HIF-2alpha translation inhibitor C76 reduced right ventricle systolic pressure (RVSP) and RV hypertrophy and inhibited RHF and fibrosis as well as obliterative pulmonary vascular remodeling in Egln1Tie2Cre mice and Sugen 5416/hypoxia PAH rats. Treatment of monocrotaline-exposed PAH rats with C76 also reversed RVSP, RV hypertrophy and pulmonary vascular remodeling, prevented RHF, and promoted survival. CONCLUSIONS: These findings demonstrate that pharmacological inhibition of HIF-2alpha is a promising novel therapeutic strategy for the treatment of severe vascular remodeling and right heart failure in PAH patients.