AIM The treatment strategy for steroid-resistant nephrotic syndrome remains uncertain at present, especially in those with calcineurin inhibitor resistance or intolerance. To date, few studies have been published using multiple combination therapy of immunosuppressive reagents for children with calcineurin inhibitor-resistant or -intolerant nephrotic syndrome. METHODS Eighteen consecutive children with steroid- and tacrolimus (TAC)-resistant (n = 10) or TAC-sensitive but frequent relapsing nephrotic syndrome (n = 8) were randomly recruited in the present study. All of them received further triple-combination therapy by cyclophosphamide (CTX, n = 6), mycophenolate mofetil (MMF, n = 5) or leflunomide (LEF, n = 7). Their clinical data were collected and efficacy of triple-combination therapy was evaluated. RESULTS Compared with previous double-combination therapy of prednisone (Pre) and TAC, the short-term remission rate in all 18 patients was significantly improved after the triple-combination therapy, while the frequent relapse rate in the following 12 months was also significantly decreased. Among three different subgroups with CTX, MMF or LEF therapy, no significant difference was found in short-term remission rate and the relapse rate within 1 year follow up by Kaplan-Meier plot. CONCLUSION Triple-combination therapy with Pre + TAC + CTX/MMF/LEF is effective for short-term response and 1 year remission, without significant additional side-effects seen in children with steroid-resistant and tacrolimus-resistant or tacrolimus-sensitive but frequently relapsing nephrotic syndrome. Further study for evaluating long-term efficacy and safety of triple-combination therapy with Pre + TAC + CTX/MMF/LEF would be necessary for these patients.