Background: Immunoglobulin A nephropathy (IgAN) is one of the most common primary glomerular diseases. Although its clinical course is usually benign, some patients develop end-stage renal failure (ESRF). The role of immunosuppressive drugs in the treatment of IgAN remains controversial. The effect of treatment with prednisolone and azathioprine and the clinical and histological parameters related to a poor outcome are examined retrospectively in this analysis. Methods: Seventy-four patients with IgAN and a follow-up period of 10 years were included in this study. Forty-one were treated with prednisolone (initially 60 mg/day) and azathioprine (initially 2 mg/kg BW/day) in gradually reduced doses for 24 ± 9 months, whereas 33 patients received no immunosuppressive drugs. The clinical course was estimated using the end-points of doubling of baseline serum creatinine and/or ESRF. The contribution of clinical and histological parameters in the clinical outcome was estimated by univariate and multivariate analyses. Results: The overall clinical courses of both groups of patients showed a rather similar pattern. Doubling of serum baseline creatinine was observed in 9 of 41 treated (22%) and in 10 of 33 untreated (30%), whereas ESRF developed in 6 treated (15%) and 6 untreated patients (18%) (p = NS). However, treated patients with heavy proteinuria (>3 g/24 h) had a significantly better outcome compared to untreated (doubling of serum creatinine in 29 vs. 78% and ESRF in 17 vs. 55%, p < 0.05). Proteinuria (p < 0.01), mean blood pressure (p < 0.02), baseline serum creatinine (p = 0.02) and severity of interstitial myofibroblast expression (p = 0.02) were identified as independent risk factors related to a poor outcome by multivariate analysis. Side effects of treatment were not uncommomn and observed in 10 (24%) patients. Conclusion: Treatment with prednisolone and azathioprine is beneficial in ameliorating the clinical course of a subset of IgAN patients with heavy proteinuria or impaired renal function. Patients with advanced renal failure and severe chronic histological lesions should not be treated by this regimen as no benefit is expected and there is a risk of side effects.