Chronic hypoxia contributes to pulmonary hypertension through complex mechanisms that include enhanced NADPH oxidase expression and reactive oxygen species generation in the lung. Stimulation of peroxisome proliferator-activated receptor gamma (PPAR) reduces the expression and activity of NADPH oxidase. Therefore, we hypothesized that activating PPAR with rosiglitazone would attenuate chronic hypoxia-induced pulmonary hypertension, in part, through suppressing NADPH oxidase-derived ROS that stimulate proliferative signaling pathways. Male C57Bl/6 mice were exposed to chronic hypoxia (CH, FiO2 10%) or room air for 3 or 5 weeks. During the last 10 days of exposure, each animal was treated daily by gavage with either the PPAR ligand, rosiglitazone (10 mg/kg/day) or with an equal volume of vehicle. CH increased: 1) right ventricular systolic pressure (RVSP), 2) right ventricle weight, 3) thickness of the walls of small pulmonary vessels, 4) superoxide production and Nox4 expression in the lung, and 5) platelet-derived growth factor receptor (PDGFR) expression and activity and reduced phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression. Treatment with rosiglitazone prevented the development of pulmonary hypertension at 3-weeks, reversed established pulmonary hypertension at 5-weeks, attenuated CH-stimulated Nox4 expression and superoxide production, PDGFR activation, and reductions in PTEN expression. Rosiglitazone also attenuated hypoxia-induced increases in Nox4 expression in pulmonary endothelial cells in vitro despite hypoxia-induced reductions in PPAR expression. Collectively, these findings indicate that PPAR ligands attenuated hypoxia-induced pulmonary vascular remodeling and hypertension by suppressing oxidative and proliferative signals providing novel insights for mechanisms underlying therapeutic effects of PPAR activation in pulmonary hypertension.