Background <p>The efficacy of rituximab (RTX) in primary membranous nephropathy (PMN) patients with high titers of anti-PLA2R antibodies (aPLA2R) is controversial. This study aimed to evaluate RTX efficacy in PMN patients with high versus low aPLA2R antibodies, and to compare RTX with traditional immunosuppressive regiments in patients with high aPLA2R antibodies.</p> Methods <p>We enrolled 118 PMN patients with positive serum aPLA2R antibodies. According to baseline aPLA2R antibody levels, patients treated with RTX were classified into low-titer (L-aPLA2R-RTX) and high-titer (H-aPLA2R-RTX) groups. Meanwhile, high aPLA2R antibody patients were divided into RTX (H-aPLA2R-RTX), tacrolimus (H-aPLA2R-TAC) and cyclophosphamide (H-aPLA2R-CTX) groups according to initial therapy. All patients were followed for 12 months. The primary outcome was complete or partial remission (CR or PR) at 12 months. Secondary outcomes included changes in laboratory parameters, relapse, and adverse events.</p> Results <p>At 12months, 36 patients (74%) in the L-aPLA2R-RTX group and 13 patients (46%) in the H-aPLA2R-RTX group achieved CR or PR (OR = 3.20, 95% CI:1.20–8.49). CR rates were 33% and 11% in the L-aPLA2R-RTX and H-aPLA2R-RTX groups (OR = 4.04, 95% CI:1.06–15.40). Regarding adverse events, there were 22% in the L-aPLA2R-RTX group and 46% in the H-aPLA2R-RTX group (<i>p</i> = 0.03). Relapse rates did not differ significantly between the two groups. At 12 months, CR rates were 11%, 25% and 62% in the H-aPLA2R-RTX, H-aPLA2R-CTX and H-aPLA2R-TAC groups, respectively (<i>p</i> = 0.001). No significant differences were observed among the three groups in terms of CR or PR rates at 12 months, relapse and adverse events.</p> Conclusion <p>PMN patients with high baseline aPLA2R antibody titers had lower remission rates with RTX compared to those with low titers. Among high-titer patients, TAC or CTX were associated with higher remission rates than RTX, particularly TAC.</p> Clinical trial number <p>Not applicable.</p>