Objectives Direct-acting antiviral agents (DAAs) have provided an ultimate treatment duration of 12 weeks for most hepatitis C virus (HCV)-infected patients. The opportunity to reduce treatment duration to 6 or 8 weeks is being evaluated. Here, the HCV viral dynamics at short times during HCV therapies and its implications for monitoring and optimizing treatment duration have been assessed. Patients and methods HCV chronic infected patients who began HCV therapy (March 2014 to June 2015) at a reference hospital of the Northwest of Spain were selected. HCV-RNA was quantified at different short time points during HCV therapy using Abbott RealTime HCV assay. Epidemiological, clinical, and virological data were recorded. Results Eleven HCV-infected patients were included; 90.9% had cirrhosis (>12.5 kPa) and 72.7% were treatment-experienced. HCV genotype 1b was the most prevalent (72.7%). All of the combinations were pegylated interferon-free and all included ribavirin. The median HCV-RNA (log IU/ml) at baseline was 5.8 (5.4–6.1); the decline between baseline and day 3, weeks 4, 8, and 12 was 3.2, 4.8, 5.1, and 5.6, respectively. Fewer than 50% of patients achieved undetectable viral load at weeks 4 and 8; however, all patients achieved a sustained virologic response at 12 weeks. Conclusion Rapid and high HCV-RNA decline was observed among HCV-infected patients under DAA-based regimens, especially for those without cirrhosis. Despite low rates of patients with undetectable HCV-RNA at weeks 4 and 8, all achieved a sustained virologic response at 12 weeks. These findings suggest that the time points to monitor HCV-RNA during DAA therapies and the treatment duration need to be optimized.