Peroxisome proliferator-activated receptors (PPARs) are members of a nuclear hormone receptor/transcription factor superfamily. PPAR signaling pathways have been reported to exert antiinflammatory effects and to attenuate the development of atherosclerosis. However, the mechanisms responsible for their antiatherosclerotic effects remain largely unknown. The present study tested the hypothesis that a PPARγ agonist may attenuate hypoxia (Hx)-induced pulmonary vascular remodeling. Wistar-Kyoto rats were randomized to normoxia (Nx) and hypobaric Hx, and were treated with and without the PPARγ agonist rosiglitazone, 2.5 mg/kg/d for 3 weeks. Pulmonary artery (PA) catheterization performed on both treated and untreated groups demonstrated no attenuation of hypoxic pulmonary hypertension (mean [± SD] PA pressures: treated group, 41.7 ± 3.01 mm Hg; untreated group, 43.9 ± 2.82 mm Hg; p = 0.12). However, morphometric analysis (vessel wall thickness/lumen radius) of tissue sections stained with hematoxylin-eosin demonstrated a marked decrease in proximal and distal PA vessel wall remodeling compared with untreated Nx and Hx controls (Nx-control mice, 0.18 ± 0.09; Nx-rosiglitazone mice, 0.21 ± 0.14 [p = 0.12] vs Hx-control mice, 0.46 ± 0.14; Hx-rosiglitazone mice, 0.23 ± 0.11 [p < 0.001]). Right ventricular hypertrophy (right ventricular/body weight × 10−6) was dramatically decreased in the Hx-rosiglitazone-treated group compared to Hx-controls (Nx, 0.0007 ± 0.0002; Hx-control, 0.0023 ± 0.0004 vs Hx-rosiglitazone, 0.0015 ± 0.0002 [p = 0.05]). The decrease in PA wall remodeling and RV hypertrophy was due to the inhibition of proliferation without an increase in apoptosis, as determined by PCNA and TUNEL staining respectively. In conclusion, the PPARγ agonist rosiglitazone exerts a significant vascular protective effect on Hx-induced PA vascular remodeling.