Caveolae and caveolin-1 participate in the transportation of cholesterol and cell signal transduction. Our previous studies showed that the inhibitory effect of calcitonin gene-related peptide (CGRP) on the vascular smooth muscle cells (VSMCs) was related to decreasing the activity of extracellular signal-regulated kinase (ERK)_1/2 and increasing the expression of caveolin-1. In the present study, we investigated the role of caveolae and caveolin-1 in proliferation of VSMCs and whether there are interaction between the caveolin-1 and ERK_1/2 in the inhibitory effect of CGRP signal pathway. VSMCs were prepared from thoracic aorta of male Sprague-Dawley rat by the classic explants method, the passage 3 ~ 10 VSMCs were used for the present study. 10% fetal bovine serum (FBS) was employed as a stimulus for the proliferation of VSMCs. β-Cyclodextrin or filipin was used to deplete cholesterol in the caveolae. Proliferation of VSMCs was estimated by methylthiazoletrazolium (MTT) assay and Flow Cytometry. Western blotting and co-immunoprecipitation were used to determine interaction of p-ERK_1/2 or caveolin-1. Results showed that CGRP significantly inhibited VSMC proliferation and down-regulated phosphorylation of ERK_1/2. Incubation of VSMCs with β-cyclodextrin or filipin promoted cells proliferation, up-regulated phosphorylation of ERK_1/2, attenuated the inhibitory action of CGRP on VSMC proliferation and decreased caveolin-1 expression. Pretreatment with CGRP increased the direct binding of cavolin-1 with phosphorylated(p-) ERK_1/2 but not non-phosphorylated ERK_1/2 in the presence of 10?S. Our results revealed that caveolae and caveolin-1 may contribute to the inhibitory effect of CGRP on the VSMC proliferation, and the mechanism may be related to the deceased nuclei translocation of p-ERK_1/2 because of the increased binding of caveolin-1 with p-ERK_1/2.