Long-term outcomes following multiple rituximab courses among children with frequently-relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. A retrospective cohort study at 16 pediatric nephrology centers from 10 countries in Asia, Europe, and North America included children with FRSDNS who received ≥2 rituximab courses. Primary outcomes were relapse-free survival and adverse events. 346 children (age 9.8 years, IQR 6.6-13.5; 73% boys) received 1149 rituximab courses. 145, 83, 50, 28, 22, and 18 children received 2, 3, 4, 5, 6 and ≥7 courses, respectively. Median follow-up was 5.9 years (IQR, 4.3-7.7). Relapse-free survival differed by treatment courses (clustered log-rank test p<0.001). Compared to the first course (10.0 months, 95% CI, 9.0-10.7), relapse-free period and relapse risk progressively improved following subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01-0.18; ps<0.001). B-cell depletion duration remained similar with repeated treatments (6.1 months, 95% CI, 6.0-6.3). Adverse events were mostly mild, most commonly hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 vs 3.3 years; p=0.05) and at first rituximab (8.0 y vs 10.0 years; p=0.01) and history of steroid resistance (28% vs 18%; p=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% vs 20%, p=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. Children receiving repeated rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable but significant complications can occur. These findings support repeated rituximab use in FRSDNS.