SummaryBackground and objectives Children with IgA nephropathy showing diffuse (Ͼ80%) mesangial proliferation are at high risk for end-stage renal failure (ESRF). A previous controlled trial showed that combination therapy consisting of prednisolone, azathioprine, heparin-warfarin, and dipyridamole early in the course of disease reduces immunologic renal injury and prevents the progression of sclerosed glomeruli. The objective of this study was to evaluate the long-term effectiveness of combination therapy in children with IgA nephropathy showing diffuse mesangial proliferation.Design, setting, participants, & measurements A secondary analysis of a multicenter, randomized, controlled trial involving 78 children with IgA nephropathy who received either 2-year combination therapy or heparin-warfarin and dipyridamole (control) therapy was conducted.Results The median duration of observation was 10 years (range, 0.5 to 18). Two of 40 patients (5%) who received combination therapy and five of 34 patients (14.7%) who received control therapy developed ESRF. A Kaplan-Meier plot of renal survival showed that the outcomes of patients in the combined therapy group were better than those in the control therapy group (log-rank P ϭ 0.03). The 10-year renal survival probability of each group was 97.1% (95% confidence interval, 81.4 to 99.6%) and 84.8% (95% confidence interval, 55.4 to 95.5%), respectively. The Cox proportional hazards model showed that the 2-year combination therapy was significantly associated with renal survival in both univariate and multivariate analyses.Conclusions Two-year combination therapy not only ameliorated the activity of the acute phase of nephritis but also improved the long-term outcome of severe childhood IgA nephropathy.