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AbstractBackground The combination of Sofosbuvir (SOF), velpatasvir (VEL), and voxilaprevir (VOX) is an effective, safe rescue therapy for patients with previous treatment failure. Direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection in diabetics with a history of hypoglycemia could improve insulin resistance due to HCV clearance. However, some studies have shown that SOF/VEL/VOX causes grade 3 hyperglycemia and other adverse events, which contradicts the findings of other DAA studies.Aim To analyze the incidence of grade 3 hyperglycemia of SOF/VEL/VOX for chronic HCV infection.Methods We searched electronic databases from the inception of each database until October 2021. A random-effects model was employed to pool data. The study was conducted according to the PRISMA guidelines, and quality assessment was performed by using the Cochrane risk-of-bias tool for randomized controlled trials (RCTs). The study protocol was registered on the INPLASY database (Registration No. 2021120109).Results Five RCTs were included in this review. Overall, 49 of 2315 patients had grade 3 hyperglycemia with a risk ratio of 0.015 (95% confidence interval, 0.010–0.020; p < .001), and the incidence risk ratio (IRR) for cirrhosis compared to without cirrhosis was 12.000 (95% confidence interval: 0.727–198.160), the HCV genotype 3–genotype 1 IRR was 4.13 (95% confidence interval: 1.52–11.22) in subgroup analysis. No significant differences were found within the other subgroups, in prior DAA treatment experience, and in treatment duration.Conclusion Although the incidence of hyperglycemia was rare in diabetic patients with HCV, it is recommended that glucose levels be closely monitored during the first 3 months of therapy and that diabetes medication be modified if necessary.