OBJECTIVE： To observe the clinical efficacy and safety of enhanced immunosuppressive therapy in the treatment of refractory nephrotic syndrome （RNS）. METHODS： Totally 76 RNS patients were selected from 2 hospitals during Jan. 2012-Mar. 2015， and then divided into control group and observation group according to random number table， with 38 cases in each group. Two groups were given Prednisone acetate tablet 50 mg， qd； decreasing to 15 mg， qd， after urine protein returned to normal. Based on it， control group was given Leflunomide tablets 50 mg， qd； decreasing to 20 mg， qd， 3 days later. Based on control group， observation group was additionally given Mycophenolate mofetil dispersible tablet 750 mg， bid； decreasing to 500 mg， qd， 3 months later. Both groups were treated for 6 months. Clinical efficacies， follow-up recurrence rate as well as renal function indexes and inflammatory cell factors before and after treatment， and the occurrence of ADR were compared between 2 groups. RESULTS： The total response rate of observation group （92.11％） was significantly higher than control group （73.68％）， and follow-up recurrence rate （5.26％） was significantly lower than control group （23.68％）， with statistical significance （P＜0.05）. Before treatment， there was no statistical significance in renal function indexes or inflammatory cell factors between 2 groups （P＞0.05）. After treatment， 24 h urinary protein quantification， urinary IL-6 and IL-8 levels of 2 groups decreased significantly， while the content of serum protein increased significantly； the observation group was significantly better than the control group， with statistical significance （P＜0.05）. There was no statistical significance in the content of serum creatinine between 2 groups before and after treatment （P＞0.05）. The incidence of ADR in the control group and the observation group was 34.21％ and 44.74％ respectively， without statistical significance between 2 groups （P＞0.05）. CONCLUSIONS： Enhanced immunosuppressive therapy in the treatment of RNS can improve renal function， reduce inflammatory reaction and long-term recurrence risk， and have good therapeutic efficacy and safety.