Receptor for advanced glycation end products (RAGE) is critical in inflammatory diseases, including diabetes and atherosclerosis. The mechanism underlying the effect of peroxisome proliferator-activated receptor (PPAR) agonist pioglitazone (PIO) on RAGE expression in coronary artery smooth muscle cells (SMCs) stimulated by high glucose concentrations remains to be elucidated. In the present study, the effect and mechanism of action of PIO on RAGE expression in SMCs was investigated following treatment with high glucose concentrations. Rat coronary artery SMCs were pretreated with PIO alone, PIO and GW9662 (a PPAR antagonist), diphenyleneiodonium (DPI; a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor) or the antioxidant pyrrolidine dithiocarbamate (PDTC; a nuclear factor-B (NF-B) inhibitor), followed by treatment with high glucose. RAGE mRNA and protein expression, reactive oxygen species (ROS) production and NF-B nuclear translocation were investigated. Glucose induced RAGE expression in a dose-dependent manner, with maximal effect at a concentration of 25 mmol/l following treatment for 48 h. PIO, DPI and PDTC reduced high glucose-induced increases in RAGE protein and mRNA expression. PIO prominently downregulated RAGE expression and inhibited high glucose-induced increases in ROS production and NF-B activation (P<0.05). Pretreatment with PIO and GW9662 did not exhibit this inhibitory effect. High glucose may stimulate RAGE expression in coronary artery SMCs through NADPH oxidase-mediated ROS generation and NF-B activation. PIO downregulated RAGE expression and inhibited ROS production and NF-B activation via PPAR activation, which may prevent the inflammatory effect of AGE/RAGE system in diabetes.