Cigarette smoke may contribute to pulmonary vascular remodeling (PVR), a result of the proliferation of pulmonary artery smooth muscle cells (PASMCs), before pulmonary hypertension in chronic obstructive pulmonary disease (COPD). Activated extracellular signal-regulated kinases 1 and 2 (ERK1/2) are considered to be involved the process of PVR. This study investigated the potential role of ERK1/2 in the proliferation of rat PASMCs (rPASMCs) and cigarette smoke-induced PVR in rats. A small interfering RNA (siRNA) against ERK1/2 (ERK1/2-siRNA) was synthesized, and it significantly reduced the expression of ERK1/2 and cyclin E1, significantly increased the proportion of cells arrested at G0/G1 phase and significantly suppressed the proliferation of rPASMCs treated with cigarette smoke extract compared with controls (all P<0.05). In rats, ERK1/2-siRNA, which was administered intranasally, also inhibited the activation of ERK1/2 and the upregulation of cyclin E1, both of which were induced after the rats were exposed to cigarette smoke for 3 months. ERK1/2-siRNA also significantly reduced PVR (observed by vessel wall thickness and the proportion of fully muscularized vessels) in cigarette smoke-exposed rats compared with a negative control siRNA (P<0.05). Collectively, these data indicated that ERK1/2-siRNA could attenuate PVR in cigarette smoke-exposed rats, and it may have therapeutic value in the treatment of COPD.