Abstract Introduction Significant advances in understanding of the molecular virology, life cycle, and pathogenesis of Hepatitis C Virus (HCV) led to the Direct-Acting Anti-viral (DAA) era of HCV therapy in 2011 (Hezode et al.,2015). It can be expected that rates of HCV-associated hepatocellular carcinoma (HCC) will decrease significantly after the widespread adoption of DAAs, However Hepatitis C patients with cirrhosis who were treated with direct-acting antivirals had increased likelihood of developing HCC (Tayyab et al., 2020) (Kozbial et al., 2016). HCC was also associated with greater liver stiffness according to transient elastography and lower platelet counts (Conti et al., 2016). The aim of this study is to investigate incidence of HCC in Egyptian HCV patients in whom other predominant HCV genotypes are prevalent and different treatment protocols followed. Methods This was a retrospective study including 400 chronic HCV patients who were following up their medical condition at Kobri El-Koba Military Hospital hepatology outpatient clinic from January 2018 to September 2019. Patients were divided into two main equal groups regarding either received HCV direct acting antivirals or not. Incidence of HCC after 18 months of follow up were compared between two groups. Its relation to hepatic fibrosis stage was calculated in both groups. Results DAA receiving group had significantly lower incidence of HCC than non DAA receiving group (control group). Eleven patients in DAA receiving group developed HCC (5.5%) compared to twenty-two patients in control group (11%) with P- value 0.04. Although there was no significant difference between two groups regarding pre-treatment prevalence of ascites, splenomegaly, or esophageal varices, DAA receiving group had statistically significant advanced hepatic fibrosis when compared to control group. Before starting treatment, DAA Receiving group shows (4.5% F0, 14% F1, 7% F2, 11.5% F3 and 63% F4) versus (20.5% F0, 14% F1, 18.5% F2, 6.5% F3 and 40.5% F4) in control group with highly significant P value 0.00. Conclusion Incidence of HCC decreased significantly after DAA in chronic HCV patients. Decreased incidence occurred despite advanced hepatic fibrosis in this group of patients.