Background:  Safety blood transfusion is based on reliable donor screening for transmissible infections such as the hepatitis C virus (HCV) infection. HCV-RNA by polymerase chain reaction (PCR) test is a gold standard test for HCV infection but with three major limitations: liability of RNA molecules, higher costs, and longer turnaround time as compared with HCV core antigen (HCVcAg) testing. Objective: To evaluate HCV core Ag as an alternative to PCR for HCV RNA to early diagnosis of HCV infection among blood donors. Patients and Methods: 4222 blood donors collected between March 2015 and July 2016 at Blood Bank Center of Najran Hospitals, Southwestern Saudia Arabia. Anti-HCV, HBsAg, syphilis and HIV were screened by third generation ELISA. Those reactive to HbsAg, syphilis and/or HIV were excluded. HCV core Ag and HCV RNA by RT-PCR were performed on 76 positive HCV-Ab sera. Results: Among total 4222 blood donors (3837 males (90.88%) and 385 females (9.12%)), 76 (1.8%) were positive for HCV-Ab (72 males; 94.74% and 4 females; 5.26%). HCV core Ag was ≥ 11 fmol/L in 65 cases (85.53%) of HCV Ab positive patients (61 males; 93.85% and 4 females; 6.15%), 3 cases with HCVcAg levels in grey zone (3-11 fmol/L) and 8 cases with HCVcAg ≤ 3 fmol/L all of both were males. HCV RNA was detected in 71/76 (93.42%) of donors with positive HCV-Ab and in 3 of 8 (37.5%) of those with positive HCV-ab and negative HCVcAg. HCVcAg has sensitivity, specificity, PPV and NPV of 97.14, 100, 100 and 99.76 values respectively at a cutoff 2.82 fmol/L compared to HCV RNA test. Conclusion:  Higher sensitivity and specificity of HCVcAg with rapid turn around time of the results, and its lower price suggested that can be used alternatively to HCV RNA test in early diagnosis of HCV infection.