Background: Hepatitis C virus is now recognized as a major world public health problem. Egypt has a very high prevalence of HCV and a high morbidity and mortality from chronic liver disease, cirrhosis, and hepatocellular carcinoma Oblective: Screening for HCV in Ismailia and identifying possible risk factors for its spread among infected patients in Ismailia governorate in Egypt. Methodology: A cross-sectional study was conducted for screening of HCV in three areas in Ismailia governorate, in the period from December 2016 till July 2018. On the basis of a specially designed protocol, standard commercially available tests and physical examinations were performed. Enzyme-linked immunosorbent assay and recombinant immunoblot assay anti HCV tests were performed for the screened persons. Risk factors were evaluated using special questionnaire administered by trained interviewers. Reported risk factors among infected subjects were compared to those subjects negative to HCV. Odds ratio based on multivariate logistic-regression model was used to identify risk factors. Results: A total of 1183 subjects were screened for HCV, of which 152 were HCV-positive and 88 of them (57.9%) were males. Mean age of the patients was 54.41 + 12.21 years. HCV patients were more likely than controls to be illiterate, unemployed and of low economic status. Furthermore, it was more common among persons sharing razors or tooth brush with other family members. Multivariate analysis showed that HCV patients were more likely than controls receiving multiple injections for treatment of chronic diseases such as diabetes mellitus or chronic renal diseases (OR= 2,11, CI=1.42-3.02), or having history of schistosomiasis (OR=1.74, CI=1.29-2.35). Furthermore, patients who received blood transfusion are having high risk of HCV (OR=3.5, CI=2.30-5.34). Meanwhile HCV was more common among women having history of delivery, whether surgical intervention was done or not. Conclusion: Our data indicate that a history of blood transfusion, women having history of delivery, or persons that received multiple injections are at high risk for HCV infection in Ismailia governorate. Therefore, focusing on medical practices and infection control in health facilities is essential for HCV transmission prevention. Furthermore, improvements in certain lifestyle patterns and customs in this region are essential to limit transmission of the disease.