Background and study aims Occult hepatitis C viral infection (OCI) may have serious complications, such as relapse, ongoing histological impairment, hepatic decompensation , hepatocellular carcinoma, and the possible risk of transmission. This study was conducted to assess the occurrence and prevalence of secondary OCI in patients with chronic hepatitis C viral infection (HCV) who received a complete course of directly acting antivirals (DAAs). Patients and methods Antiviral therapy consisted of sofosbuvir + daclatasvir ± ribavirin for 12 weeks to 90 treatment-naive, compensated, chronic HCV patients. Plasma and peripheral blood mononuclear cells (PBMCs) were tested for HCV RNA viral load by quantitative, reverse transcription, real-time PCR at 8, 12 (Group I, n = 45), and 24 (Group II, n = 45) weeks after treatment initiation. Results By week 8, only 2 and 7 patients were positive for HCV RNA in plasma and PBMCs, respectively. No HCV RNA was detected by weeks 12 or 24 in the PBMCs of Groups I and II, respectively. Older age was significantly associated with HCV RNA positivity in plasma and PBMCs (n = 8) at week 8 compared with HCV RNA negativity (n = 82). No other significant differences were observed for any other variables. Conclusion The development of secondary OCI among easy-to-treat patients following a full course of DAA treatment doesn't exist, hence, we do not recommend testing the HCV RNA in the PBMCs after complete course of treatment in this patient category. The detection of HCV RNA in PBMCs is recommended as a confirmatory test of cure following a shortened DAA treatment regimen.