Children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) often require multiple courses of rituximab. However, long-term effects from repeated treatments remain unknown. In this international, multicenter study of 346 children receiving 1149 courses of rituximab, the risk of relapse decreased and relapse-free survival significantly improved with repeated treatments. Important side effects, including hypogammaglobulinemia, neutropenia, and infections, were mostly mild, but significant adverse events could occur. The incidence of side effects did not increase with more treatment courses nor a higher cumulative dose of rituximab. These findings suggest that repeating rituximab therapy is an effective and reasonably safe approach for most children with FRSDNS.