In the present study we examine whether hepatitis C virus (HCV) infection status influences glomerular pathologic findings in renal allografts and its effect on graft outcome. Renal allograft biopsies performed between January 1991 and June 1999 were considered. Exclusion criteria were insufficient sample, unknown HCV serological status at time of biopsy and final diagnosis of acute rejection. Light microscopy and immunofluorescence studies were performed on all biopsies. According to a predefined protocol, electron microscopy was carried out. Of 138 eligible renal allograft biopsies, 42 fulfilled at least one exclusion criterion. Of 96 biopsies selected for the study, 44 (45.8%) were from HCV-positive and 52 from HCV-negative recipients. Renal biopsy was performed 74 ± 55 and 60 ± 39 months after transplantation in HCV-positive and HCV-negative groups, respectively (p = 0.12). Of 44 HCV-positive biopsies, 20 (45.4%) showed membranoproliferative glomerulonephritis (MPGN) (16 type I and 4 type III). Conversely, in HCV-negative biopsies there were only three cases of MPGN (2 type I and 1 type III). De novo membranous GN (MGN) was diagnosed in 8/44 (18.2%) HCV-positive and in 4/52 (7.7%) HCV-negative cases. The prevalence of chronic transplant glomerulopathy was similar in HCV-positive and HCV-negative groups (11.4% and 11.5%, respectively). The prognosis of de novo GN (either MPGN or MGN) was worse in HCV-positive than in HCV-negative recipients (relative risk 4.89; 95% confidence interval, 1.15–20.69; p = 0.03). By multivariate analysis, HCV-positive serology infection was the only independent predictor of graft loss (relative risk 2.64; 95% confidence interval, 1.35–5.17; p = 0.005). In diagnostic renal allograft biopsies the presence of de novo immune-mediated glomerulonephritis, especially type I MPGN, is strongly associated with HCV infection and results in accelerated loss of the graft.