The aim of this study is to identify the influence of chronic HCV infection on development of interstitial fibrosis (IF) in renal allografts and evaluate if pretransplant interferon-alpha (IFN-alpha) therapy has an effect on IF. The development of IF and graft outcome were compared between anti-HCV positive (n = 28) and anti-HCV negative (n = 30) recipients. The influence of IFN-alpha therapy on IF and graft survival was compared between anti-HCV positive recipients who received pre-transplant IFN-alpha therapy (n = 15, group 1) and anti-HCV positive recipients who did not receive IFN-alpha therapy (n = 13, group 2). Recipients with anti-HCV antibodies had higher incidences of IF and shorter graft survival than did recipients without anti-HCV antibodies (p < 0.05 for both). Development of IF was higher in group 2 recipients, and patients in group 1 had longer graft survivals (p < 0.05 for both). Patients with positive HCV-RNA had higher grades of tubular TGF-beta1 expression than did patients with negative HCV-RNA (p < 0.05). Expression of tubular TGF-beta1 was lower in group 1 patients when compared with group 2 patients (p < 0.001). In conclusion, we suggested that HCV infection may have a triggering effect on the development of IF in renal allografts by augmenting renal expression of TGF-beta1.