Background: In some genes, Polymorphisms may have an influence on the persistence of HCV infection, HCV replication, or spontaneous clearance of the virus. This study was carried out to investigate the association of chemokines CCL2 gene polymorphism with the susceptibility to HCV infection with high-resolution techniques in Egyptian families. Methods: A total of 75 Egyptian families with a total of 291 subjects in this study were recruited from different Egyptian populations from Dakahlia governorate and were classified into 2 groups: 146 infected persons with chronic hepatitis C (CHC), 145 subjects as a healthy control group. All subjects were genotyped for rs13900 C/T SNP of CCL2 gene using allelic discrimination real time PCR (RT-PCR) technique. Results: The allele carriage of at least one copy of C allele of CCL2 rs13900 C/T polymorphism was significantly lower in the positive group when compared to that of negative group (OR = 0.4169, 95% CI 0.1830 to 0.9496, p 0.0372) indicating that The C allele of rs13900 C/T polymorphism is protective allele against development of chronic HCV while the allele carriage of homozygotes TT of CCL2 rs13900 C/T polymorphism was significantly higher in the positive group when compared to that of negative group (OR = 2.3986, 95% CI 1.0530 to 5.4635, p 0.0372) indicating that The C allele of rs13900 C/T polymorphism is protective allele against development of chronic HCV. Conclusions: HCV infection is associated with rs13900 C/T SNP of CCL2 gene in the Egyptian families.