Objective ·To evaluate and compare the clinical efficacy and safety of rituximab (RTX) monotherapy and RTX combined with glucocorticoids in the treatment of high-risk primary membranous nephropathy (PMN). Methods ·A retrospective cohort study was conducted to include 87 high-risk PMN patients who received RTX treatment in Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, between December 2018 and February 2024. Patients were divided into RTX monotherapy group and RTX combined with glucocorticoid group (combination therapy group) according to their treatment regimens. After adjusting for confounding factors using propensity score matching (PSM), intention-to-treat (ITT) and per-protocol (PP) analyses were performed to evaluate the primary efficacy outcomes. Results ·A total of 58 patients were included after PSM, with 29 in each group. At 12 months after treatment, ITT analysis showed that the overall remission and complete remission (CR) of RTX monotherapy were 72.41% and 20.69% respectively, compared to 79.31% and 55.17% in the combination therapy group. The difference in CR rates between the two groups was statistically significant (P=0.007). The differences in serum creatinine, blood urea nitrogen, and estimated glomerular filtration rate (eGFR) were not statistically significant. However, the 24-hour urinary protein levels in the combination therapy group were significantly lower than those in the RTX monotherapy group (P=0.024). PP analysis showed that the CR rate of the combination therapy group was also significantly higher than that of the RTX monotherapy group (P=0.026). During follow-up, serum creatinine levels and eGFR remained stable in both groups. The incidence of adverse events was comparable between the two groups, with no statistically significant differences. Conclusion ·Compared with RTX monotherapy, RTX combined with glucocorticoids significantly improves the CR rate in high-risk PMN patients without increasing the incidence of adverse events. This combination regimen appears to be an effective treatment strategy, though its long-term efficacy and safety warrant further confirmation through large-scale prospective studies.