Hypoxia-induced pulmonary hypertension (HPH) is a progressive disease characterized by a sustained, elevated pulmonary arterial pressure and vascular remodeling. The latter pathogenesis mainly involves overproliferation of pulmonary artery smooth muscle cells (PASMCs). Fibroblast growth factor 21 (FGF21) has recently emerged as a novel regulator that prevents cardiac hypertrophic remodeling. However, its possible role in pulmonary remodeling remains unclear. The activation of peroxisome proliferator activated receptor γ (PPARγ) is reported to attenuate HPH by suppressing proliferative signals. Loss of PPARγ in the lung contributes to abnormal proliferation of PASMCs. FGF21 is a key regulator of PPARγ activity in adipocytes, but its role has not been elucidated in PASMCs. Therefore, we hypothesized that FGF21 may confer therapeutic effects in HPH by upregulating the expression of PPARγ. Sprague-Dawley rats were exposed to hypoxia and treated with FGF21 for 4 weeks. In parallel, hypoxic conditions and FGF21 were administered to rat PASMCs for 48?h. FGF21 attenuated the hypoxia-induced elevation in mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy (RVH), medial thickening and overproliferation of PASMCs. Furthermore, FGF21 abrogated the reductions in PPARγ expression and increases in TNF-α, IL-1 and IL-6 levels in PASMC culture media. Collectively, these results demonstrate that FGF21 could potentially attenuate the pathogenic derangements of HPH by targeting PPARγ and inflammatory cytokines.