We hypothesized that antiviral efficacy [sustained virologic response (SVR)] has improved in recent years in the transplant setting. Our aim was to assess whether the efficacy of pegylated interferon (PegIFN)–ribavirin (Rbv) has improved over time. One hundred seven liver transplant patients [74% men, 55.5 years old (range: 37.5–69.5), 86% genotype 1a or 1b] were treated with PegIFN-Rbv for 355 (16–623) days at 20.1 (1.7–132.6) months after transplantation. Tacrolimus was used in 61%. Sixty-seven percent had baseline F3–F4 (cirrhosis: 20.5%). Donor age was 49 (12–78) years. SVR was achieved in 39 (36.5%) patients, with worse results achieved in recent years (2001–2003: n = 27, 46.5%; 2004: n = 23, 43.5%; 2005: n = 21, 35%; 2006 to January 2007: n = 36, 24%; P = 0.043). Variables associated with SVR in the univariate analysis included donor age, baseline viremia and cirrhosis, bilirubin levels, rapid virologic response and early virologic response (EVR), premature discontinuation of PegIFN or Rbv, and accumulated Rbv dose. In the multivariate analysis, the variables in the model were EVR [odds ratio (OR): 0.08, 95% confidence interval (CI): 0.016–0.414, P = 0.002] and donor age (OR: 1.039, 95% CI: 1.008–1.071, P = 0.01). Variables that had changed over time included donor age, baseline viremia, disease severity (cirrhosis, baseline bilirubin, and leukocyte and platelet counts), interval between transplantation and therapy, and use of growth factors. In the multivariate analysis, variables independently changing were donor age (OR: 1.041, 95% CI: 1.013–1.071, P = 0.004), duration from transplantation to antiviral therapy (OR: 1.001, 95% CI: 1.000–1.001, P = 0.013), and baseline leukocyte count (OR: 1.000, 95% CI: 1.000–1.000, P = 0.034). In conclusion, the efficacy of antiviral therapy with PegIFN-Rbv has worsened over time, at least in our center. The increase in donor age and greater proportion of patients treated at advanced stages of disease are potential causes. Liver Transpl 15:738–746, 2009. © 2009 AASLD.