Aim To explore a disintergrin and metalloproteinase 17 (ADAM17) regulating the protective effect of calcitonin gene-related peptide (CGRP) against proliferation of vascular smooth muscle cell (VSMC) and its mechanism.Methods The rat thoracic aortic smooth muscle cell line (A10VSMC) was used as the object of study. RNA interference was adopted to reduce ADAM17 expression. Western blot and real-time quantitative PCR were used to detect the expression levels of protein and mRNA. Methylthiazolyldiphenyl-tetrazolium bromide assay was used to evaluate cell viability of VSMC.Results CGRP could markedly attenuate angiotensin Ⅱ-induced VSMC proliferation. There were significant increases in expression levels of ADAM17 protein and mRNA in VSMC stimulated with angiotensin Ⅱ for 24 hours. Pretreatment with CGRP for 30 minutes significantly reduced the expression levels of ADAM17 protein and mRNA, whereas the effects could be reversed by CGRP receptor antagonist CGRP8-37. The results of RNA interference showed that ADAM17 siRNA significantly inhibitted angiotensin Ⅱ-mediated VSMC proliferation. Conclusion The reduction of ADAM17 expression may be the mechanism by which CGRP inhibits angiotensin Ⅱ-mediated VSMC proliferation.