Aim To explore the effects of rapamycin liposomes (RL) on the migration of human aortic vascular smooth muscle cells (HA-VSMC) induced by oxidized low density lipoprotein (ox-LDL) and its mechanism related to S100 calcium binding protein A4 (S100A4). Methods Vascular smooth muscle cells were transfected with lentivirus knockdown S100A4 gene, and then added puromycin to screen stable strain of S100A4 gene knockdown. Vascular smooth muscle cells were treated with 50 mg/L ox-LDL, and different doses of RL (3,6 and 12 mg/L) were added to observe the effect on cell migration before and after treatment. Cell migration was detected by cell scratch method and Transwell, and the expression of S100A4, phosphorylated phosphatidylinositol 3-kinase (p-PI3K), phosphorylated protein kinase B (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), typeⅠcollagen protein (COLⅠ), and vimentin were detected by Western blot. Results After 48 h treatment with ox-LDL, compared with the blank control group, the expression of S100A4, p-PI3K, p-Akt, p-mTOR, COLⅠ and vimentin was significantly increased (P＜0.05), and the speed of cell migration was significantly accelerated (P＜0.05). Compared with ox-LDL group, different doses of RL significantly inhibited the expression of S100A4, p-PI3K, p-Akt, p-mTOR, COLⅠ and vimentin and significantly inhibited cell migration after 48 h treatment (P＜0.05), of which 6 mg/L and 12 mg/L of RL had more significant inhibitory effects (P＜0.05). After S100A4 gene knockdown, the cell migration rate was significantly reduced (P＜0.05). Conclusion RL can significantly inhibit the migration of HA-VSMC induced by ox-LDL, which may be related to the down-regulation of S100A4, p-PI3K, p-Akt, p-mTOR, COLⅠ and vimentin expression by RL.