Background Rituximab, a chimeric anti-CD20 monoclonal antibody, is an effective treatment in steroid-dependent nephrotic syndrome (SDNS). However, some patients develop adverse reactions. Case-Diagnosis/Treatment Patient 1, a 14-year-old boy with SDNS since the age of 2, was treated with oral prednisone, cyclosporine A (CsA) and mycophenolate mofetil. A first infusion of rituximab at age 12 years was well tolerated, but this was followed by a prolonged relapse unresponsive to oral prednisone, mycophenolate mofetil and CsA. A second rituximab infusion was attempted, but treatment was interrupted due to severe dyspnea. Treatment with a humanized anti-CD20 monoclonal antibody, ofatumumab, was then attempted. The patient experienced a mild allergic reaction and maintained remission despite interruption of all treatment at >12 months of follow-up. Patient 2, a 3-year-old boy who presented at 18 months with nephrotic syndrome initially resistant to treatment with oral prednisone, was given with three intravenous boluses of methylprednisolone followed by CsA and achieved remission. Upon steroid discontinuation, the NS relapsed. Prednisone was restarted and treatment with a single dose of rituximab was never completed due to a severe allergic reaction. Ofatumumab infusion was uneventful, and he maintained remission during the follow-up period (>12 months) despite interruption of prednisone therapy. B cells reappeared at 7 months in both patients. Conclusions Ofatumumab may be a therapeutic option in severe forms of NS with allergy to rituximab.