To observe the efficacy and safety of multi-target (tacrolimus+ mycophenolate mofetil+ prednisone) therapy for type III+ V and IV+ V type lupus nephritis. A total of 56 patients with lupus nephritis were randomly divided into a treatment group receiving multi-target treatment and a control group receiving intravenous cyclophosphamide combined with prednisone treatment, with 28 patients in each group. Clinical indicators and adverse reactions were observed before and 4, 12, 24, 48 and 72 weeks after treatment. One patient withdrew from the treatment group and two patients from the control group due to adverse reactions within 72 weeks of treatment. Compared with those before treatment, urine protein quantification, ds-DNA antibody titer and systemic lupus erythematosus disease activity index (SLEDAI) scores were significantly decreased at 24 h after 72 weeks of treatment in both groups (P< 0.05). The total remission rate was 85.2% in the treatment group and 57.7% in the control group (P< 0.05) and dte total response rate was 59.3% and 30.8%, respectively (P< 0.05). Multiple target treatment of type III+ V or IV+ V type lupus nephritis has a higher total remission rate, a shorter treatment time, and a lower incidence of adverse reactions than cyclophosphamide and prednisone combined therapy.