Pulmonary hypertension (PH) is characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs), leading to dysregulated vascular remodeling. Cigarette smoke (CS) is a common risk factor causing PH, and our previous study showed that CS extract (CSE) stimulated abnormal PASMC proliferation. However, the molecular mechanism remains unclear. In systemic circulation, vascular remodeling in some diseases is associated with upregulation of Kruppel-like factor 4 (KLF4), which stimulates the proliferation of vascular smooth muscle cells. We therefore hypothesized that upregulation of KLF4 may play a role in pulmonary vascular remodeling and the development of PH. Our results showed that KLF4 expression was increased significantly in remodeled pulmonary arteries from the rat smoking model of pulmonary vascular remodeling, compared with controls. In human PASMCs in vitro, KLF4 knockdown by gene silencing decreased proliferation and migration significantly. At the same time, it inhibited the CSE-induced increase of AKT phosphorylation. These results indicate that KLF4 contributes to CS-induced pulmonary vascular remodeling, and that KLF4 gene knockdown may be a useful therapeutic intervention for PH.