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Introduction: Leptin is one of the new adipokines that reflects the pathological status of liver tissue in the chronic hepatitis C virus (HCV). This study aimed to investigate the leptin and liver enzymes responses to aerobic exercise (AE) in overweight nondiabetics with HCV.Material and methods: Forty nondiabetic non-cirrhotic HCV men aged 40-60 years old with a body mass index (BMI) varied from 25-29.9 kg/m2 were divided randomly to study and control groups. The study group (n = 20) received a 3-session continuous moderate-intensity AE per week for 12 weeks while the control group (n = 20) were advised to maintain their normal level of physical activity. Pre and post measurements of weight, BMI, waist circumference, fasting blood glucose (FBG), alanine transaminase (ALT), aspartate transaminase (AST), and leptin were measured for all forty patients.Results: Statistical ANOVA analysis revealed a post-treatment significant statistical decrease of all variables within the study group (p < 0.05) while the control group showed a non-significant difference of all measurements. Post-treatment between-group analysis showed a significant statistical difference in FBG, ALT, AST, and leptin in favor of the study group.Conclusions: To restore the normal hepatic cellular functions and to prevent HCV-induced hepatic fibrosis, AE is a strong therapeutic modality that lowers leptin levels via weight maintenance and/or loss, increased glucose uptake, and declined liver enzymes.