Background. Hepatitis C has been associated with an increased incidence of diabetes mellitus (DM) following renal transplantation (RT). Methods. Patients who underwent RT between 1985 and 2001 were excluded if they showed DM prior to RT, graft survival of less than 90 days, and unknown anti-HCV status (n = 15). Two groups (G1 and G2) were distinguished according to the immunosuppressive regimen: G1 (transplanted 1985-1996) received steroids, azathioprine, and cyclosporine (n = 330), whereas G2 (1997-2000) received new drugs in several combinations (MMF in 87% and/or tacrolimus in 35% [n = 240]). Patients with HCV antibodies pre- and/or post-RT were considered HCV-positive. Post-RT DM requiring prolonged treatment with oral antidiabetics or insulin (>1 month) was assessed using Kaplan-Meier curves and Cox analysis. Results. G2 patients were significantly older, had a greater body mass index (BMI), and suffered significantly less from acute rejection episodes during the first year than G1 patients. Furthermore, fewer required maintenance steroids. HCV-positivity was more common in G1 than in G2 (n = 96, 29.1% vs n = 27, 11.3%). Six G2 patients were successfully treated with interferon pre-RT, achieving negative PCR-HCV status (maintained post-RT). DM incidence at 4 years was similar in G1 and G2 (8.8% and 8.2%). G1 HCV-positive patients showed a greater risk of developing DM than HCV-negative patients (28.0% vs 6.2% at 10 years; P = .001). In G1, multivariate analysis showed that age, BMI, and HCV-positivity were significant risk factors predicting DM (relative risk, 5.7; 95% confidence interval 2.7-12). In G2 patients, HCV was not associated with an increased risk of DM; in the multivariate analysis only age appeared to be a risk factor. Conclusions. The reported relationship between hepatitis C and post-RT DM was not observed among patients receiving new immunosuppressive treatments. Confirmation of this finding requires extended follow up. The reduced use of steroids and effective pre-RT use of interferon may also be responsible for the benefit.