Hepatitis C virus (HCV) recurs in nearly all patients after liver transplantation. This recurrence is associated with progressive fibrosis and graft loss. It remains unclear whether the natural course of HCV recurrence is altered in patients who undergo living donor liver transplantation (LDLT). We conducted a prospective, controlled trial using protocol liver biopsies to evaluate the histologic outcome of recurrent HCV in 23 patients who underwent LDLT and 53 patients who underwent transplantation with a deceased donor liver (DDLT) during the same period of time. Patients who did not survive at least 6 months after transplantation or who had hepatocellular carcinoma or any other coexistent liver disease were excluded from analysis. All patients underwent protocol liver biopsy at 6 months and at 12 months and at yearly intervals thereafter. The mean age, sex, racial distribution, and serum HCV RNA and the percentage of patients with genotype 1 were similar in the 2 groups of patients. The model for end-stage liver disease score at the time of transplantation was slightly lower in patients who underwent LDLT, but this difference was not significant. The distribution of immunosuppression agents used, the mean doses of calcineurin agents, the use of mycophenolate mofetil, and the dose and tapering schedule for prednisone were similar in both groups of patients. The mean duration of follow-up was 40 months. No significant difference in either graft or patient survival or the percentage of patients who developed acute rejection was noted in the 2 groups of patients. At 48 months, graft and patient survival were 82% and 82% and 75% and 79% for patients who underwent DDLT and LDLT, respectively. The degree of hepatic inflammation increased stepwise over 3 years but was not significantly different in the 2 patient groups. In contrast, the mean fibrosis score and the percentage of patients with fibrosis increased stepwise after DDLT but appeared to plateau 12 months after LDLT. At 36 months, fibrosis was present in 78% of DDLT patients, and mean fibrosis score was 1.9, compared with 59% with fibrosis and a mean score of.9 after LDLT. In conclusion, these data strongly suggest that fibrosis progression from recurrent HCV is not more severe in patients after LDLT.