Background and objectives Different rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy. Design, setting, participants, & measurements Twenty-eight participants from the NICE cohort received two infusions of 1-g rituximab at 2-week intervals, whereas 27 participants from the Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Membranous Nephropathy (GEMRITUX) cohort received two infusions of 375 mg/m 2 at 1-week interval. We measured serum rituximab levels and compared remission at month 6 and before any treatment modification and analyzed factors associated with remission and relapses. Results Remissions occurred in 18 (64%) versus eight (30%) from the NICE and GEMRITUX cohort ( P =0.02) at month 6, respectively, and in 24 (86%) versus 18 (67%) participants ( P =0.12) before treatment modification, respectively. Median time to remission was 3 [interquartile range (IQR), 3–9] and 9 [IQR, 6–12] months for NICE and GEMRITUX cohorts respectively ( P =0.01). Participants from the NICE cohort had higher circulating level of rituximab and lower CD19 counts (3.3 µg/L [IQR, 0.0–10.8] versus 0.0 [IQR, 0.0–0.0] P <0.001 and 0.0 [IQR, 0.0–2.0] versus 16.5 [IQR, 2.5–31.0] P <0.001) at month 3, lower level of anti-PLA2R1 antibodies at month 6 (0.0 [IQR, 0.0–8.0] versus 8.3 [IQR, 0.0–73.5] P =0.03). In the combined study population, lower epitope spreading at diagnosis and higher rituximab levels at month 3 were associated with remissions at month 6 (13/26 (50%) versus 22/29 (76%) P =0.05 and 2.2 µg/ml [IQR, 0.0–10.9] versus 0.0 µg/ml [IQR, 0.0–0.0] P <0.001 respectively). All non-spreaders entered into remission whatever the protocol. Eight of the 41 participants who reached remission had relapses. Epitope spreading at diagnosis (8/8 (100%) versus 16/33 (48%) P =0.01) and incomplete depletion of anti-PLA2R1 antibodies at month 6 (4/8 (50%) versus 5/33 (9%) P =0.05) were associated with relapses. Conclusions Our work suggests that higher dose rituximab protocol is more effective on depletion of B-cells and lack of epitope spreading is associated with remission of membranous nephropathy.