Introduction: Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling with subsequent right ventricular (RV) failure. Hypothesis: The p38-alpha mitogen-activated protein kinase (p38-α MAPK) plays a pathogenic role in PAH. This work investigated the effects of a selective p38-alpha MAPK inhibitor, named LASSBio-1824, on hypoxia + SU5416 -induced PAH. Methods: Male Wistar rats (180-220 g) were exposed to 3 weeks of hypoxia and i.p. injection of VEGFR antagonist (SU5416; 20 mg/kg/week). Experimental groups were: Control + vehicle (DMSO), SuHx + vehicle (PAH group) and SuHx + LASSBio-1824 (20 mg/kg/day for 2 weeks). Results: Pulmonary acceleration time (ms) was reduced from 44.7 ± 1.1 (control) to 20.6 ± 1.7 in SuHx + vehicle group (P < 0.05) and restored to 38.9 ± 2.9 in SuHx + LASSBio-1824 group (P< 0.05). RV systolic pressures (mmHg) were increased from 30.1 ± 3.2 (control) to 109.5 ± 7.5 in SuHx group and reduced to 47.5 ± 5.3 after treatment with LASSBio-1824 (P < 0.05). The medial wall thickness of distal pulmonary arterioles (< 50 μm) was measured by immunohistochemistry for alpha-SMA expression which was increased from 40.7 ± 3.5 % (control) to 64.1 ± 3.1 % in PAH animals (P < 0.05) and was reduced in the treated group (52.2 ± 2.9). Acetylcholine-induced maximal relaxation (% ) in pulmonary arteries was reduced from 77.9 ± 5.2 to 17.2 ± 3.5 in PAH group. LASSBio-1824 increased that response to 67.8 ± 5.6 % (P < 0.05), indicating the ame- lioration of endothelial function. RV hypertrophy was detected because its wall thickness (mm) increased from 0.56 ± 0.02 (control) to 1.3 ± 0.03 in SuHx + vehicle group (P < 0.05) and the ratio between RV and left ventricle + septum increased from 1.50 ± 0.03 to 2.0 ± 0.2. Treatment with LASSBio-1824 significantly reduced the RV hypertrophy (ratio of 1.7 ± 0.07). Conclusion: The inhibition of p38-alpha MAPK isoform by LASSBio-1824 represents an impor- tant approach for the treatment of PAH in the future, which improves the underlying remodeling and inflammation processes.