Cigarette smoke has been considered a major contributor to the pathogenesis of chronic obstructive pulmonary disease (COPD). In COPD patients, the airway smooth muscle layer has been observed to be markedly thickened and the proliferation of airway smooth muscle cells (ASMCs) was therefore used by the present study as a model to assess the impact of cigarette smoke extract (CSE). ASMCs were exposed to various concentrations of CSE and the proliferation of the cells was analyzed by an MTT assay. Furthermore, the expression levels of calreticulin and CCAAT/enhancer-binding protein alpha (C/EBP-) in CSE-stimulated ASMCs were determined by polymerase chain reaction and western blot analyses. In addition, the effects of RNA interference (RNAi) to knockdown calreticulin and/or C/EBP- on ASMC proliferation were studied. CSE was found to promote the proliferation of ASMCs, which was associated with increased expression of calreticulin and decreased expression of C/EBP-. Knockdown of calreticulin resulted in the upregulation of C/EBP- and inhibition of cell proliferation, while simultaneous knockdown of C/EBP- promoted cell proliferation. The present study revealed that CSE promoted the proliferation of ASMCs, which was mediated by inhibition of C/EBP-. These findings shed new light on airway remodeling in COPD and may provide novel approaches for therapies.