Background: A challenging healthcare concern is the infection caused by the Hepatitis C virus. The Egyptian Ministry of Health adopted many assertive preventive measures to significantly decrease the spread of the disease. These measures focused on all methods of HCV transmission. Human saliva may contain HCV ribonucleic acid (RNA), according to recent research emphasizing the need for further study. Aim: to assess the presence of HCV RNA in human saliva and how it relates to serum HCV RNA along with treatment outcomes using direct-acting antivirals. Methods: Chronic HCV patients who showed positive HCV viremia and were eligible to be treated according to the Egyptian HCV guidelines enrolled in the study. Assessment of both serum and salivary HCV RNA have been done pre- and post-treatment. Results: Enrollment was done for 50 patients. The mean age was 52.56±12.93 years and the majority (54%) were males. Most of the patients were not cirrhotic either by Fibrosis-4 score (Fib-4) (2.69±1.98) or by ultrasound (Only 18% are cirrhotic). Serum HCV RNA was positive in all cases (100%); however, there are only three positive salivary RNA (6%). Seventy-two percent of patients fall in the easy-to-treat category according to Egyptian protocol for HCV treatment. All patients achieved a sustained virological response (100%) with no positive RNA results in both serum and saliva. Conclusion: HCV could be present in human saliva, but its prevalence is low. Saliva has low risk of HCV transmission and it is not recommended to use salivary RNA to diagnose or follow up HCV.