Introduction – Since May 2019, the initial prescription of direct-acting antivirals (DAAs) for the treatment of hepatitis C, which was initially restricted to specialists practicing in hospitals, has been extended to all physicians for patients eligible for simplified care coverage. Our objectives were to describe the temporal and regional variations in the proportion of first-line DAA prescriptions issued by private general practitioners (GPs) and to study the associated factors in mainland France between 2019 and 2022. Methods – Adults residing in mainland France who received an initial prescription for AAD between May 2019 and December 2022 were identified in the National Health Data System (SNDS). The percentage of individuals with a first-time ODA prescription from a GP was described, both overall and by region, along with the factors associated with this type of prescription among individuals eligible for a simplified treatment plan (logistic regression). Results – Among the 22,353 individuals identified, 1,101 (4.9%) received a first-time prescription for AAD from a GP. The percentage of first-time AAD prescriptions by a GP ranged from 2.7% in the Pays de la Loire region to 8.3% in the Grand Est region. Among the 15,938 individuals eligible for a simplified treatment protocol, this type of prescription applied to 855 individuals (5.4%). In a multivariate analysis adjusted for region of residence, first-time DAA prescriptions by a general practitioner were more common among individuals receiving opioid substitution therapy, and less common among those receiving state medical aid (AME) or residing in a medical desert. Conclusion – The first-time prescription of AADs in primary care remains very rare in mainland France, with marked regional differences. With the goal of eliminating hepatitis C, it is important to support and encourage this practice, particularly in areas where the local healthcare network remains sufficient.