Objective ·To investigate whether the efficacy of tacrolimus (TAC) monotherapy is non-inferior to TAC combined with glucocorticoids (TAC+GC) in the treatment of idiopathic membranous nephropathy (IMN), and evaluate its safety. Methods ·This pilot study was conducted by the Department of Renal Rheumatology and Immunology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine from November 2017 to March 2021. High-risk patients with biopsy-proven IMN were recruited and randomly divided into two groups: TAC monotherapy group only received TAC treatment [an initial dose of 0.050?0.075 mg/(kg·d), maintaining trough blood concentration of 5?10 ng/mL]; TAC combined with GC group (TAC+GC group) received TAC (the same as TAC monotherapy group) combined with prednisone [an initial dose of 0.5 mg/(kg·d) for 8?12 weeks, then tapered until complete withdrawal]. The baseline data of the two groups of patients were collected, and the efficacy indicators and safety indicators of the patients were observed and recorded during the visit. The primary end points of the study were the total remission rate and complete remission rate of proteinuria at 24 weeks of treatment. The secondary end points included the efficacy indicators [24 h urinary protein quantification, serum albumin level and estimated glomerular filtration rate level at 24 weeks of treatment] and the incidence of adverse events (elevated blood glucose, thrombosis and infection). Non-inferiority test was used to compare the total remission rate of proteinuria in the two groups, and the non-inferiority margin was set as -10%. Fisher's precision probability test was used to compare the total remission rate, complete remission rate and adverse events rate of the two groups of patients. Non parametric tests were used to compare the differences of the percentage changes of the efficacy indicators from baseline values after treatment between the two groups. Results ·A total of 36 IMN patients were enrolled, with 18 in TAC monotherapy group and 18 in TAC+GC group. There was no statistically significant difference between the baseline data of the two groups. During the treatment, 1 case was lost in TAC monotherapy group and 3 cases in TAC+GC group. Finally, 36 patients were included in the full analysis set (FAS), 32 patients were included in the per protocol set (PPS), and 36 patients were included in the safety set. The results of non-inferiority test showed that it was not observed that the efficacy of TAC monotherapy was not inferior to that of TAC combined with GC. The risk difference of total remission rate of proteinuria in the two groups was 0 (95%CI -31.9?31.9, P=0.269), and the lower limit was below the non-inferiority margin. In FAS and PPS, there was no significant difference in complete remission rate and total remission rate between the two groups at 24 weeks of treatment, and no significant difference in the percentage changes of the efficacy indicators from baseline values after treatment between the two groups. Ten patients (4 cases in TAC monotherapy group, and 6 cases in TAC+GC group) developed elevated blood glucose over the period of treatment, with no significant difference between the two groups; one patient (TAC+GC group) developed right upper extremity venous thrombosis. Conclusion ·This pilot study finds that the total remission rate and complete remission rate of the two groups are similar at 24 weeks of treatment. The frequency of adverse events in TAC monotherapy group is relatively lower than that in TAC combined with GC group. However, the available data cannot prove that the efficacy of TAC monotherapy is non-inferior to that of TAC combined with GC in the treatment of IMN.