The role of immunosuppressive therapy in the management of IgA nephropathy (IgAN) remains controversial. No consensus has yet emerged on the specific treatment of IgAN and this is mostly related to the lack of complete understanding of the multifactorial pathogenesis of the disease. Choice of appropriate therapeutic agents is further limited by the difficulty in identifying patients who would most likely benefit from therapy. Immunosuppressive therapy has not been recommended in patients with isolated hematuria and well preserved renal function because of their generally favourable prognosis and there are no clinical trials in this area. Considering that mild IgAN may be an early stage of the disease and can be reversed by immunosuppressive agents we have used prednisolone and azathioprine in patients with isolated hematuria in a prospective, randomized, controlled study since 1988. In this prospective study we have evaluated the effect of prednisolone with azathioprine on the clinical course of IgAN and its impact on histologic parameters and prevention of progression in patients with isolated hematuria. We studied 43 biopsy-proven IgAN patients (29 males and 14 females, aged between 13-63 years, mean age 28+/-6) with isolated hematuria and well-preserved renal function (Ccr 89.2+/-10.2 ml/min). The patients were assigned to two groups: 21 patients received prednisolone (40 mg/day) and azathioprine (100 mg/day) orally for four months (group A) and 22 patients received no specific treatment for IgAN and served as a control group (group B). In Group A prednisolone was reduced to 20 mg/day at the end of the second month, then slowly tapered over a two-month period and stopped. The median duration of follow-up was 60 months (range 12-120 months). At the end of the therapy hematuria disappeared in 17 patients. In three patients who did not respond to therapy, microscopic hematuria persisted. Of the 22 patients of group B, three had episodes of gross hematuria and proteinuria >500 mg/day. No significant changes in biochemical profile were observed in either group. Thirteen patients (eight from the treated, five from the untreated group) underwent a repeat biopsy after 12+/-6 months (range 10-25). An improvement of histopathological features was noted in Group A, while deterioration was noted in Group B. We conclude that early treatment with prednisolone and azathioprine appears to be beneficial in preventing the progression of immunologic renal injury and in improving histopathological features in IgAN patients with isolated hematuria.