The prevalence of HCV infection is higher among prisoners than in the general population. The introduction of HCV direct-acting antivirals (DAA) holds the potential to improve clinical outcomes also in inmates. However, treatment of hepatitis C in inmates has to face several clinical and logistical issues which are peculiar of prison environment. Recommendations on the management of HCV infection specific for the penitentiary setting in the DAA era remain scant. The Italian Society for Penitentiary Medicine and Healthcare has, therefore, issued these recommendations, to provide clinicians with a guide for the comprehensive management of HCV infection in the restriction setting, taking into account its peculiar characteristics. Dedicated diagnostic and treatment procedures should be established in each prison. In particular, the use of DAAs appears crucial to provide patients with an effective therapeutic option, able to overcome the limitations of IFN-based regimens with a short period of treatment. DAA treatment should be initiated as soon as possible in all eligible subjects with the aim to cure the patient, as well as to limit the transmission of HCV infection both inside the penitentiary system and to the free community, once the inmates ends his/her release. Importantly, efforts should be made to open a discussion with regulatory bodies, to define specific regulations aimed to guarantee wide access to effective therapies of all eligible patients, to optimize the management of and the adherence to the HCV treatment, and to ensure the therapeutic continuity after discharge from prison.