Introduction: Right ventricle (RV) remodeling and vascular dysfunction are present in pulmonary arterial hypertension (PAH). Hypothesis: This work focuses on the benefits of the association of human umbilical cord mesenchymal stem cell (hMSC) with lodenafil, a PDE5 inhibitor, on PAH in rats. Methods: Experiments were in accordance with the Animal Care and Use Committee at the Federal University of Rio de Janeiro. PAH was induced in male Wistar rats by exposure to hypoxia (10% O 2 ) during 3 weeks plus i.p . injection of an antagonist of VEGF receptor (SU5416; 20 mg/kg/week). Animals were randomly divided (n=6): PAH + vehicle; PAH + lodenafil (gavage, 10 mg/kg); PAH + lodenafil + hMSC (5x10 5 , i.v.) for 14 days. Results: PAH induced the reduction of the ratio of pulmonary acceleration time and RV ejection time from 0.42 ± 0.01 to 0.24 ± 0.01, which was recovered to 0.31 ± 0.01 after treatment with lodenafil + hMSC. RV afterload confirmed by increased systolic pressure (mmHg) of 52.1 ± 8.8 (contro: 24.0 ± 3.1) was normalized to 29.6 ± 2.2 with association. Pulmonary arteries wall thickness (%) measured by immunohistochemistry for alpha-SMA was increased by HAP from 44.7 ± 1.4 to 64.2 ± 1.2 and was partial (57.7 ± 1.4) or totally recovered (47.3 ± 0.9) after treatment with lodenafil and association, respectively. Increased RV collagen fraction (%) of 7.4 ± 1.2 was induced by HAP when compared to control group (1.9 ± 0.1) and although lodenafil did not alter this parameter (6.6 ± 0.9) its association with hMSC restored to 2.7 ± 0.4. Increased RV wall thickness (mm) observed in PAH (from 0.60 ± 0.02 to 1.05 ± 0.13) recovered to 0.58 ± 0.04 after treatment with association. ERK1/2 expression evaluated by western blot analysis recovered from 0.79 ± 0.07 to 0.12 ± 0.06, which reinforced the reduction of cellular proliferation by treatment with lodenafil + hMSC. RV expression of p38 mitogen associated protein kinase was measured by stained area quantification using immunohistochemistry (%) was also increased in PAH group (from 9.4 ± 2.5 to 31.4 ± 2.2, p < 0.05) and the association of lodenafil + hMSC reduced to 11.4 ± 3.4. Conclusions: Therapy of hMSC and lodenafil improved cardiac remodeling and vascular dysfunction in SuHx-PAH rats, representing an important approach for the future treatment of PAH.