The assessment of individual risk of fibrosis progression in patients with chronic hepatitis C is an unmet clinical need. Recent genome-wide association studies have highlighted several genetic alterations as predictive risk factors of rapid fibrosis progression in chronic hepatitis C. However, most of these results require verification, and whether the combined use of these genetic predictors can assess the risk of fibrosis progression remains unclear. Therefore, genetic risk factors associated with fibrosis progression were analyzed in 176 chronic hepatitis C patients who did not achieve sustained virological response by interferon-based therapy and linked to the fibrosis progression rate (FPR). FPR was determined in all patients by paired liver biopsy performed before and after therapy (mean interval: 6.2 years). Mean FPR in patients with IL28B (rs8099917) TG/GG and PNPLA3 (rs738409) CG/GG were significantly higher than in those with IL28B TT (FPR: 0.144 vs. 0.034, P < 0.001) and PNPLA3 CC (FPR: 0.10 vs. 0.018, P = 0.005), respectively. IL28B TG/GG [hazard ratio (HR): 3.9, P = 0.001] and PNPLA3 CG/GG (HR: 3.1, P = 0.04) remained independent predictors of rapid fibrosis progression upon multivariate analysis together with average alanine aminotransferase after interferon therapy ≥40 IU/l (HR: 4.2, P = 0.002). Based on these data, we developed a new clinical score predicting the risk of fibrosis progression (FPR-score). The FPR-score identified subgroups of patients with a low (FPR: 0.005), intermediate (FPR: 0.103, P < 0.001), and high (FPR: 0.197, P < 0.001) risk of fibrosis progression. In conclusion, IL28B and PNPLA3 genotypes are associated with rapid fibrosis progression, and the FPR-score identifies patients who has a high risk of fibrosis progression and require urgent antiviral treatment.