The limited knowledge of the cellular mediators of renal scarring hampers progress in the management of progressive chronic renal failure (CRF). We have studied 38 patients with biopsy-proven mesangial IgA nephropathy with emphasis on attempting to define the role of myofibroblasts(α-smooth muscle actin/SMA-positive cells) in renal scarring. In 18 untreated patients, correlations were undertaken between known histological parameters of progression as well as the presence of myofibroblasts in tissues and the clinical outcome. α-SMA staining by an avidin-biotin-peroxidase method was confined to a large extent to the vascular smooth muscle cells of normal kidneys but extended to the tubulointerstitium and periglomerular space in scarred kidneys. Mild glomerular staining was also noted. The interstitial immunostain followed a similar distribution to that of interstitial type III collagen. Morphometric analysis showed the interstitial αSMA staining to be a reliable histological predictor of outcome as it discriminated between progressors and non-progressors (χ²=4.923, P=0.026). The intensity of the interstitial α-SMA staining correlated with renal functional outcome; inversely with the reciprocal of serum creatinine slopes (r=-0.466, P<0.025) and positively with the serum creatinine value at the end of the observation period (r=0.704, P<0.00l). Other histological parameters that correlated with outcome included the degree of tubulointerstitial (TI) inflammatory infiltrate (r=-0.425, P<0.05 with 1/Cr slope and r=0.760, P< with serum creatinine) and the intensity of the TI staining for collagen IV (r=-0.567 and 0.667 respectively). In 20 patients treated with prednisolone and azathioprine, a second renal biopsy showed the persistence of interstitial myofibroblasts in the absence of progressive fibrosis. In conclusion, staining of renal biopsies of patients with mesangial IgA for α-SMA-positive cells may identify the myofibroblasts as important mediators of TI scarring and have useful prognostic implications.