Fibrosis recurrence after liver transplantation (LT) for hepatitis C virus (HCV) is a universal event and strongly determines a patient's prognosis. The recipient risk factors for fibrosis recurrence are still poorly defined. Here we assess a genetic risk score as a predictor of fibrosis after LT. The cirrhosis risk score (CRS), which comprises allele variants in 7 genes (adaptorrelated protein complex 3 S2, aquaporin 2, antizyme inhibitor 1, degenerative spermatocyte homolog 1 lipid desaturase, syntaxin binding protein 5-like, toll-like receptor 4, and transient receptor potential cation channel M5), was calculated for 137 patients who underwent LT for HCV infection and experienced HCV reinfection of the graft. The patients were stratified into 3 CRS categories: <0.5, 0.5 to 0.7, and >0.7. All patients underwent protocol biopsy after LT (median follow-up ΒΌ 5 years), and liver fibrosis was assessed according to the Desmet and Scheuer score. The data were analyzed with univariate and multivariate analyses. The results showed that the highest CRS category was strongly associated with the presence of F2 or F3 fibrosis in protocol biopsy samples 1, 3, and 5 years after LT (P ΒΌ 0.006, P ΒΌ 0.001, and P ΒΌ 0.02, respectively). Overall, 75.0% of the patients with a CRS > 0.7 developed at least F2 fibrosis, whereas 51.5% developed F3 fibrosis during follow-up. The predictive value of the CRS for fibrosis progression was independent of known clinical risk factors, including the age of the donor, the sex of the recipient, and the occurrence of acute rejection. A Kaplan-Meier analysis confirmed the prognostic value of the CRS with respect to the recurrence of severe liver fibrosis in HCV-infected patients after LT (log rank ΒΌ 6.23, P ΒΌ 0.03). In conclusion, the genetic signature of the recipient predicts the likelihood of severe liver fibrosis in the graft after HCV recurrence. The CRS might help with early clinical decision making (eg, the selection of patients for antiviral therapy after LT).