Aim To study the effect and mechanism of Nε-carboxymethyllysine (CML) on vascular smooth muscle cells (VSMC) foam cells formation. Methods Primary VSMC were extracted from the aorta of C57BL/6J mice using tissue affixing method and identified; Primary smooth muscle cells of 3～9 passages were divided into control group, oxidized low-density lipoprotein (ox-LDL) (50 mg/L) group, 1,0, and 100 μmol/L concentrations of CML and ox-LDL co-stimulation group. The levels of total cholesterol (TC), free cholesterol (FC) and cholesteryl esters (CE) were determined by a cholesterol content assay kit; the primary VSMC were divided into four groups:control group, ox-LDL-induced model group, and ox-LDL co-stimulated with CML group, RAGE siRNA silencing group. Western blot and qRT-PCR was used to detect receptor for advanced glycation end products (RAGE) and cholesterol efflux end regulator ATP binding cassette transporter A1 (ABCA1); The degree of foaming of smooth muscle cells in each group was detected by oil red O staining and oil red extraction experiments. Results Compared with control group, CML significantly increased smooth muscle intracellular TC, CE and FC levels; Cholesterol efflux experiments showed that cholesterol efflux rate decreased with increasing CML concentration; Western blot showed that compared with the control group, RAGE in the CML group was significantly higher, ABCA1 was significantly lower, and RAGE siRNA decreased expression of RAGE, and increased ABCA1 levels. Oil red staining showed that ox-LDL could promote lipid accumulation in smooth muscle cells, and CML could enhance its effect. Conclusion CML/RAGE inhibits VSMC cholesterol efflux, induces vascular smooth muscle cell derived-foam cells formation.