Intravenous cyclophosphamide (IVCP) has been shown to be effective in lupus nephritis. This is a randomized controlled trial to compare the effectiveness of IVCP with oral cyclophosphamide (OCP) in patients with steroid-dependent (SD) idiopathic nephrotic syndrome (INS). Forty-seven consecutive children who were SD were randomized to receive either OCP (2 mg/kg per dayx12 weeks) or IVCP (500 mg/m(2) per month IVx6 months) after achieving a steroid-induced remission. The response was evaluated in terms of remission, change in steroid response status, duration of remission (i.e., proteinuria-free days), side effects, and compliance. Of the 47, IVCP was given to 26 children and OCP to 21 children. The demographic data, histopathology, biochemical profile, and duration of follow-up in the two groups were similar. On Kaplan-Meier survival analysis, the median proteinura-free time was 360+/-88 days compared with 96+/-88 days in the OCP group (values median+/-SE, log rank P=0.05). The actuarial cumulative sustained remission in our study was 73% in IVCP compared with 38.1% in OCP at 6 months after therapy, but was almost identical (18.6% in IVCP vs. 19%in OCP) after 2 years. Thus in our study the overall improvement in steroid response category from SD to sustained remission, infrequent relapser, and frequent relapser (88% in IVCP vs. 57% in OCP) was significantly better in the IVCP group, although the number of children with persistent remission tended to be similar at 2 years. Furthermore, the response was observed with a 40% lower cumulative dose than OCP. Hence, we conclude that IVCP is a safe and effective therapeutic modality in children with INS who are SD.