Objective: There have been only a few studies concerning oral prednisolone and mizoribine therapy for diffuse IgA nephritis (IgAN). We evaluated the efficacy of prednisolone and mizoribine therapy for diffuse IgAN. Methods: We enrolled 34 patients who had been diagnosed as having diffuse IgAN with severe proteinuria during the period from 1992 to 1999. Following diagnostic renal biopsy, the patients were treated with prednisolone, mizoribine, warfarin and dilazep dihydrochloride. The clinical features, laboratory data and pathological findings between pre- and post-therapy were investigated. Results: The mean urinary protein excretion after 6 months of treatment had decreased significantly compared to pre-therapy. The incidence of hematuria in post-therapy was lower than that of pre-therapy. The grading index decreased significantly from 4.8 ± 2.1 at the first biopsy to 2.3 ± 1.7 at the second biopsy (p < 0.001) and the staging index decreased significantly from 4.1 ± 1.9 at the first biopsy to 2.7 ± 2.4 at the second biopsy (p < 0.05). Macrophage infiltration and α-smooth muscle actin-positive cells in the glomerulus and interstitial region decreased significantly in post-therapy compared with pre-therapy. At the most recent follow-up, none of the 34 patients had renal insufficiency. Conclusions: Our study suggested that prednisolone and mizoribine therapy is effective for those patients with the risk of progression of IgAN.