Aim To investigate the mechanism and signal pathways of xeroderma pigmentosum group D(XPD) gene on the proliferation of human umbilical vein smooth muscle cell (HUVSMC) induced by ox-LDL. Methods HUVSMCs were transfected with the plasmids of pEGFP-N2/XPD using Lipofectamine 2000, and subsequently silent mTOR gene. MTT and EdU assay was used to detect the cell proliferation. Flow cytometry was used to examine the cell apoptosis. The expression of XPD, lectin-like oxidized low-density lipoprotein receptor 1(LOX-1), mTOR, phospho-mTOR, Bcl-2 and Bax was measured by Western blot. Results The expression of XPD and Bax protein was down-regulated in ox-LDL group (P＜0.05), while the expression of LOX-1, mTOR, Bcl-2 protein and the ratio of Bcl-2/Bax was significantly up-regulated (P＜0.05), compared with control group. Cell proliferation of ox-LDL group increased obviously (P＜0.05). After transfected with the pEGFP-N2/XPD plasmid, the expression of Bax was significantly up-regulated, while the expression of LOX-1, mTOR, Bcl-2 and the ratio of Bcl-2/Bax were significantly down-regulated (P＜0.05). Flow cytometry showed that overexpression of XPD increased the apoptosis rate of HUVSMC (P＜0.05). MTT and BdU showed that cell proliferation of pEGFP-N2/XPD group reduced compared with control group (P＜0.05). Compared with control group, the expression of LOX-1 was significantly down-regulated in siRNA mTOR group (P＜0.05). Conclusion XPD can inhibit HUVSMC proliferation and promote its apoptosis, and reduce the effect of ox-LDL promoting proliferation of HUVSMC via the mTOR/LOX-1 pathway. XPD may be the target of treatment of atherosclerosis.