Background and aim of work: A significant proportion of cancer is attributable to DNA damage caused by chronic infection and inflammation. Because hepatitis C virus (HCV) cause chronic infection and inflammatory disease, the aim of the present study was to investigate DNA damage in patients with HCV infection compared with controls and whether there is an association between the level of peripheral DNA damage and hepatocellular carcinoma (HCC). We also aimed to correlate the findings of DNA damage with the clinical and laboratory parameters and to investigate if the comet score is a possible marker for HCC detection. Methods: Sixty nine patients with HCV (14 patients without cirrhosis, 28 patients with cirrhosis, 27 patients with HCC) and 29 healthy subjects were included in the study. The DNA damage in lymphocytes was determined using the alkaline comet assay. Results: Comet scores were significantly higher in HCC and cirrhotic patients compared to healthy controls and HCV patients without cirrhosis. Patients who presented with DNA damage had 4.7 fold risk of having HCC more than those with undamaged DNA. At a cutoff of 215, comet scores had 89% sensitivity for detection of HCC. Conclusions: Ongoing DNA damage in peripheral blood lymphocytes was detected in complicated HCV patients. Thus such a test could be used to detect which patient is at higher risk to develop HCC.