Proliferation of vascular smooth muscle cells (VSMC) represents an essential event in the developement of diabetic atherosclerosis. Previous studies suggest that several cytokines and growth factors mediate the proliferation capability in VSMC from diabetic animals. In addition, advanced glycation end products (AGE) and receptor for AGE (RAGE) are important for pathologic features of diabetic complications. In the present study, we attempted to clarify the roles of AGE and RAGE in the proliferation of VSMC using streptozotocin (STZ)-treated rat sera and aortic SMC prepared from non-diabetic rats. AGE levels increased in the diabetic sera, which enhanced the growth of VSMC in proportion to their diabetic periods. AGE-bovine serum albumin (BSA) prepared in vitro also exhibited a stimulatory effect on VSMC growth. The endocytic uptake of AGE and enhanced RAGE expression in VSMC after culture with diabetic sera were observed. In addition, anti-AGE and anti-RAGE antibodies inhibited these stimulatory effects on VSMC growth. These findings suggest that AGE in diabetic rat sera may cause an enhanced effect on VSMC proliferation. However, the concentrations of AGE in diabetic sera were much lower than that of AGE-BSA which demonstrated a significant stimulatory effect on VSMC growth. The magnitude of the VSMC growth-enhancement by the diabetic sera was markedly greater than that by the AGE-BSA solution. In conclusion, the AGE-RAGE interaction in VSMC, in addition to growth factors induced by AGE, contributes to the stimulatory effect of diabetic sera on VSMC proliferation which can accelerate atherosclerosis.