〔Abstract〕 Objective To investigate the effect of leflunomide(LEF) on the expression of associated autophagy genes in synoviocytes of rheumatoid arthritis(RA) by regulating HIF-1α signal pathway. Methods Three generations of RA synovial cells were divided into blank control group, LEF group and Tripterygium wilfordii polyglycosides group. The blank control group was added with the same volume of DMEM culture medium. The drug group was treated with LEF(concentration 0.2 mg/ml) and Tripterygium wilfordii polyglycosides(concentration 0.03 mg/ml), the proliferation and apoptosis of synovial cells were detected by flow cytometry, the expression of IL-1β, TNF-α, ANGPTL-4 and VEGF was detected by ELISA, the expression of HIF-1α mRNA was detected by qRT-PCR, and the expression of HIF-1 α, Beclin-1 and BNIP3 protein was detected by Western blot. Results Compared with Tripterygium wilfordii polyglycosides group, the expression of IL-1 α, TNF-α, ANGPTL-4 and VEGF in synovial supernatant of LEF group decreased; compared with the blank control group, the expression of HIF-1α mRNA in synovial cells of LEF group and Tripterygium wilfordii polyglycosides group decreased, and the effect of LEF group was the most obvious; compared with the blank control group, the protein expressions of HIF-1α, Beclin-1 and BNIP3 in synovial cells of LEF group and Tripterygium wilfordii polyglycosides group decreased, and the effect of LEF group was the most obvious. Conclusion LEF can inhibit the expression of inflammatory factors in RA synovial cells, inhibit HIF-1α signaling pathway, inhibit the expression of autophagy-related genes Beclin-1 and BNIP3, and improve the pathological state of synovitis.