Background: Chronic liver disease has a significant impact on the survival of renal transplant recipients. At present, there is no safe and efficacious therapy of chronic hepatitis C (HCV) after renal transplantation. Interferon-based therapy in renal transplant recipients remains a controversial issue, as it has been associated with a high risk of rejection and poor efficacy. Aim: To assess the safety and efficacy of PEG-IFN and ribavirin combination therapy in post-renal transplant HCV-infected patients. Methods: Thirty two adult renal transplant recipients at two centers in Saudi Arabia, >12 months after transplant surgery with confirmed HCV and evidence of histological disease (METAVIR >A2/F2; >F3=17) were recruited in a pilot open-label trial with PEGIFN-alpha-2a (135-180 μg/week, based on GFR [MDRD equation]) plus ribavirin (200-1200 mg/day, based on GFR). Safety and laboratory assessments were performed weekly for 4 weeks, then 2-weekly for 8 weeks, and then 6-weekly for 36 weeks. Subjects were more male (57%), mean age 47 ± 13(years±SD), BMI 26.4±5.2, genotype (G1=21, G4=11) and mean HCV RNA 6.4± 0.9 log10 IU/mL. Early (EVR) and sustained virologic response (SVR) were defined as a 2-log10 reduction from baseline or undetectable HCV RNA (< 50 IU/mL) at treatment week 12, and undetectable HCV RNA at 24 weeks of off-treatment follow-up, respectively. Renal biopsy was performed in patients with a 20% increase in serum creatinine from pretreatment levels. Results: All patients completed the treatment periods and 21 completed all study assessments. Dose reductions of PEGIFN and ribavirin were required in 36% and 54%, respectively for hematological side effects. EVR was similar between G1 (58.8%) and G4 (45.4%) patients (P = 0.08). Overall, 62.5%, 47 % and 37.5% achieved EVR, end-of-treatment response and SVR, respectively. No patient experienced rejection episodes during or after therapy from the 9 (28%) who required renal biopsy. There was no difference in the pre-treatment and end of assessment serum creatinine (110 ± 41 vs. 125 ± 52 μmol/L, P = 0.16). Three of the non responder patients developed liver decompensation. Conclusions: PEGIFN/ribavirin therapy in renal recipients is safe in low risk for rejection patients, with good efficacy in the treatment of chronic HCV. Treatment-related non-renal side effects are common and may contribute to sub-optimal virologic response.