OBJECTIVES: The health and economic burden of Hepatitis C virus (HCV) infection in chronic kidney disease (CKD) patients in the United States is significant. GZR (NS3/4A protease inhibitor)/EBR (NS5A inhibitor) have been shown to be highly effective and well tolerated in HCV G1 patients with advanced CKD. Our objective was to project the clinical and economic impact of GZR/EBR compared with no treatment (NoTx) and pegylated interferon plus ribavirin (peg-IFN/RBV). METHODS: A state-transition model of chronic HCV, liver disease, and CKD was developed to project lifetime incidence of liver complications, including hepatocellular carcinoma (HCC), life expectancy, discounted quality-adjusted life years (QALY), and discounted disease cost (COST) (2015 US dollars). Efficacy of GZR/EBR was obtained from C-SURFER, a phase 2/3, randomized, double-blind, placebo-controlled trial of GZR/EBR in HCV G1 patients in CKD stages 4/5. In the pre-specified primary population, the proportion of patients achieving sustained viral response 12 weeks after the completion of therapy was 0.99 (0.95–1.00). Based on the results of a meta-analysis, we assumed an efficacy of 0.60 (0.47–0.71) for peg-IFN/RBV. Data on baseline characteristics of the simulated patients were obtained from NHANES. Natural history parameters were estimated from published studies. Drawing parameter values from well-defined statistical distributions, one-thousand Monte Carlo simulations were conducted to estimate mean incidence and 95% uncertainty intervals. RESULTS: Incidence of HCC was 1.11% (0.05–4.61) with GZR/EBR compared with 23.20% (8.79–42.30) when NoTx was used and 9.83% (2.85–21.26) with peg-IFN/RBV. Compared with NoTx and peg-IFN/RBV, GZR/EBR increased QALYs by 2.38 (1.62–3.30) and 1.41 (0.76–2.22) years, respectively. COST of $138,304 (122,047–155,296) was lowest with GZR/EBR. In comparison, Peg-IFN/RBV’s COST was $144,562 (126,553–165,999) and COST with NoTx was $162,846 (141,624–187,487). CONCLUSIONS: Our model predicts that GZR/EBR will reduce the incidence of liver-related complications and disease costs and prolong QALYs in patients with HCV G1 infection and CKD.