Abstract Background Airway remodeling is a key feature of asthma, characterized by increased proliferation of airway smooth muscle cells (ASMCs). S100A8 is a calcium‑binding protein with a potential to regulate cell proliferation. Here, the effect of exogenous S100A8 protein on the proliferation of ASMCs induced by platelet‑derived growth factor (PDGF) and the underlying molecular mechanism was investigated. Methods Rat ASMCs were cultured with or without a neutralizing antibody to the receptor for advanced glycation end‑products (RAGE), a potential receptor for S100A8 protein. Purified recombinant rat S100A8 protein was then added into the cultured cells, and the proliferation of ASMCs induced by PDGF was detected by colorimetric‑based WST‑8 assay and ampedance‑based xCELLigence proliferation assay. The expression levels of RAGE in ASMCs were analyzed using western blotting assay. Results Results showed that exogenous S100A8 inhibited the PDGF‑induced proliferation of rat ASMCs in a dose‑ dependent manner with the maximal effect at 1 μg/ml in vitro. Furthermore, when ASMCs was pre‑treated with anti‑RAGE neutralizing antibody, the inhibitory effect of S100A8 on PDGF‑induced proliferation was significantly sup‑ pressed. In addition, neither the treatment with S100A8 or PDGF alone nor the pre‑treatment with rS100A8 followed by PDGF stimulation affected the expression levels of RAGE. Conclusions Our study demonstrated that S100A8 inhibits PDGF‑induced ASMCs proliferation in a manner depend‑ ent on membrane receptor RAGE.