Aim To estimate the effect of total panax notoginsenosides (TPNS) on expression of interleukin-17A (IL-17A), interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) in apolipoprotein E-knockout (ApoE－/－) mice.Methods ApoE－/－ mice were fed with a high fat, high cholesterol diet containing 15% fat and 0.25% cholesterol. At 20 weeks of age, ApoE－/－ mice were randomized into three groups, the model group, the TPNS low dose group and the TPNS high dose group. Mice in TPNS low dose group were given oral doses of TPNS at 40 mg/kg, once a day for 8 weeks. Mice in TPNS high dose group were given oral doses of TPNS at 120 mg/kg, once a day for 8 weeks. Mice in model group were given an equal volume of distilled water orally. After 8 weeks, blood and aortas were obtained. Serum levels of lipid were analyzed, ratio of plaque area to vessel area and the expression of IL-17A, IL-10 and TNF-α were examined by histological staining and ELISA respectively. Results It was observed in our study that serum levels of lipid, ratio of plaque area to vessel area, and expressions of IL-17A and TNF-α were lower in mice which were given TPNS. Serum total cholesterol, triglyceride and low density lipoprotein cholesterol in model group was 28.2±4.0 mmol/L, 2.08±0.17 mmol/L and 10.0±1.9 mmol/L respectively , which were 16.4±2.2 mmol/L, 1.36±0.23 mmol/L and 5.9±1.2 mmol/L in TPNS high dose group (P＜0.001) and 20.4±1.1 mmol/L (P＜0.05), 1.91±0.25 mmol/L (P＞0.05) and 8.0±0.8 mmol/L (P＜0.05) in TPNS low dose group. The ratio of plaque area to vessel area was 31.3%±5.1% in model group, 14.1%±5.0% in TPNS high dose group and 24.2%±4.9% in TPNS low dose group (P＜0.05). High dose of TPNS could down-regulate the expressions of IL-17A and TNF-α in spleen mononuclearcell(IL-17A 18.1±1.5 vs 22.8±3.1,P＜0.05; TNF-α 18.3±1.2 vs 22.9±0.7, P＜0.001). On the other hand, high dose of TPNS could up-regulate the expression of IL-10 in spleen mononuclearcell (40.9±2.2 vs 36.3±2.8, P＜0.05). Conclusion These results suggest that TPNS could prevent atherosclerosis by lowering serum lipid levels and regulating spleen mononuclearcell IL-17A, IL-10 and TNF-α expression. TPNS may have implications for clinical treatment of atherosclerosis vascular disease.