Abstract: Objective To observe the efficacy of leflunomide combined with methotrexate in the treatment of rheumatoid arthritis(RA)patients and the changes of serum vascular endothelial growth factor(VEGF)and vascular endothelial growth factor receptor 2(VEGFR2). Methods A total of 110 patients with RA were randomly divided into treatment group and control group, with 55 cases in each group. The control group was treated with methotrexate, while the treatment group was treated with leflunomide combined with methotrexate. After 3 months of treatment, the curative effect, safety and clinical symptom before and after treatment were evaluated. The levels of erythrocyte sedimentation rate(ESR), rheumatoid factor(RF), VEGF and VEGFR2 were compared between the two groups. Results The total effective rate of the treatment group was significantly higher than that of the control group(94.55% versus 78.18%, P<0.05). After 3 months of treatment, morning stiffness time in the two groups was significantly shorter than that before treatment(P< 0.05). The number of joint swelling and tenderness in the two groups were significantly reduced than those before treatment(P< 0.05). The levels of ESR, RF, VEGF and VEGFR2 after treatment in the two groups were significantly lower(P< 0.05). The morning stiffness time in the treatment group was significantly shorter than that in the control group(P< 0.05). The number of joint swelling and tenderness in the treatment group were significantly less than those in the control group(P< 0.05). The levels of ESR, RF, VEGF and VEGFR2 in the treatment group were significantly lower than those in the control group(P< 0.05). Conclusion Leflunomide combined with methotrexate is safe - and effective in the treatment of RA, which can effectively improve the clinical symptoms of RA, andreduce the levels of serum VEGF and VEGFR2.