Phosphatase and tensin homolog (PTEN) plays an important role in the pathogenesis of hypoxic pulmonary hypertension (HPH). A decrease in PTEN expression is associated with the hypermethylation of its promoter. However, whether the demethylation of the PTEN gene could attenuate HPH remains unknown. 5-Aza-2 '-deoxycytidine (5-Aza-dC) is a DNA methyltransferase (DNMT) inhibitor. The present study was designed to investigate the effects and mechanisms of 5-Aza-dC on HPH. The proliferation, migration and apoptosis of rat pulmonary artery smooth muscle cells (PASMCs) induced by hypoxia and treated with 5-Aza-dC were detected. The expression of PTEN and DNMTs and the PTEN methylation status of PASMCs were detected. SD rats were randomly divided into normal group, hypoxia group and hypoxia + 5-Aza-dC group. The expression of PTEN was decreased, the expression of DNMTs was increased, and the methylation status of PTEN was increased in hypoxia-induced PASMCs. However, 5-Aza-dC can rescue the decreased PTEN, inhibit DNMT levels in a dose-dependent manner and suppress PTEN methylation. Furthermore, the demethylation of PTEN, which was induced by 5-Aza-dC, inhibited the proliferation, migration and promoted apoptosis in PASMCs. In vivo studies further demonstrated that the expression of PTEN, mean pulmonary artery pressure and right ventricular hypertrophy index in HPH rats was attenuated by 5-Aza-dC. 5-Aza-dC also suppressed the expression of DNMTs and PTEN methylation in the lungs of HPH rats. These results indicated that PTEN promoter methylation status is involved in HPH. 5-Aza-dC, as a DNMT inhibitor, has the potential to attenuate HPH via demethylation of the PTEN promoter.