Aim To explore the effect of lysine methyltransferase SET8 on proliferation and migration of rat vascular smooth muscle cells (VSMC). Methods Vascular smooth muscle cells were obtained from rat thoracic aorta, and then randomly divided into control group, empty plasmid group and SET8-shRNA group. The expression of SET8, E-cadherin was detected by RT-PCR and Western blot, cell proliferation was measured by MTT assay, cell migration was measured by transwell asssy. Results The expression of SET8 in SET8-shRNA group was lower than that in normal control group and empty plasmid group (P＜0.05). MTT results showed that the proliferation activity of 12 h, 24 h, 36 h and 48 h in SET8-shRNA group was significantly lower than that in normal control group and empty plasmid group (P＜0.05). The Transwell assay showed that the cell migration ability in SET8-shRNA group was decreased (P＜0.05). The expression of E-cadherin mRNA and protein in SET8-shRNA group was significantly higher than that in normal control group and empty plasmid group (P＜0.05). Conclusion Interference with SET8 gene expression could promote the expression of E-cadherin and inhibit the proliferation and migration of rat vascular smooth muscle cells.