Objective To evaluate the clinical efficacy of rituximab (RTX) in patients with phospholipase A2 receptor (PLA2R)-negative primary membranous nephropathy (PMN) presenting as nephrotic syndrome, and to identify predictors for treatment efficacy. Methods This retrospective cohort study included 19 biopsy-proven PLA2R-negative PMN patients with nephrotic syndrome who received RTX at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine between March 2020 and March 2024. Additionally, 38 PLA2R-positive PMN patients with nephrotic syndrome who received RTX were matched as controls. All patients were followed for at least 6 months (median = 12 months) to evaluate the clinical efficacy of RTX in both groups and to analyze potential predictors of treatment efficacy in PLA2R-negative MN patients. Results In PLA2R-negative PMN patients treated with RTX for 12 months, the 24-hour proteinuria significantly decreased from (9.8±4.3) g/d to (2.6±2.6) g/d and serum albumin increased from (20.3±4.3) g/L to (36.4±7.1) g/L (P<0.05). The overall change in estimated glomerular filtration rate showed no statistical significance [(90.7±30.0) mL·min^-1·1.73 m^-2 vs. (84.4±22.19) mL·min^-1·1.73 m^-2] (P>0.05). Overall remission rates in the PLA2R-negative group at 3 months (57.89%), 6 months (57.89%), 12 months (85.71%) were comparable to those in the PLA2R-positive group (P>0.05). However, the complete remission rate was significantly higher in the PLA2R-negative group at 3 months (21.5% vs. 0%, P=0.009 8) and 6 months (36.84% vs. 10.53%, P=0.030 5), indicating statistical significance. The univariate logistic regression analysis showed that factors influencing clinical remission at 12 months of RTX treatment in PLA2R-negative PMN patients were 3-month 24-hour proteinuria (OR=0.993, P=0.047 1) and 3-month serum albumin (OR=1.309, P=0.048 8). Conclusion RTX treatment is effective in treating PLA2R-negative PMN. Compared with the PLA2R-positive group, the overall remission rate at 12 months was comparable, with a slightly higher complete remission rate at 3 months. The 3-month 24-hour proteinuria and 3-month serum albumin levels may serve as potential predictors for clinical remission at 12 months in PLA2R-negative PMN patients.