Summary Background/objective Pharmaceutical care is needed in hepatitis C virus (HCV)‐infected patients treated with direct‐acting antivirals (DAA). We describe the implementation of a comprehensive pharmaceutical care programme (CPCP) for HCV‐infected patients treated with DAA in a tertiary‐care hospital and provide data about health outcomes and costs. Methods Quasi‐experimental study between 1 April 2015 and 30 June 2016. A group of hospital pharmacists collaborating on HCV infection implemented interventional measures for validation of drug prescriptions, detection of clinically relevant drug‐drug interactions and adverse drug events (ADEs), and patient education. Quality, health and cost‐effectiveness outcomes were evaluated. Results A total of 1070 patients were enrolled. Pharmacists made 327 interventions that led to the prevention of 299 (91.4%) medication errors, 16 of which were grade G‐H (NCC MERP classification). The main reasons for the pharmacist's intervention were management of 143 drug‐drug interactions. The overall sustained virologic response at week 12 posttreatment (SVR12) rate was 93.0% (95% CI 91.4‐94.6). The SVR12 was higher than 90.0% in all populations, except in genotype 3 patients (86.0%, 95% CI 78.7‐93.9), decompensated cirrhotic patients (81.1%, 95% CI 69.7‐92.6) and transplant recipients (86.8%, 95% CI 76.7‐96.9). ADEs occurred in 85.5% of the study patients, but only 1.0% (11 patients) experienced an ADE that led to premature discontinuation. The total cost of treatment was €18 279 225 (€17 083 per patient). The most cost‐effective treatment was selected in 93.1% of patients. Conclusions The implementation of a CPCP developed by hospital pharmacists in patients treated with DAAs for HCV infection is an effective approach that improves patient safety and education. The active involvement of the pharmacist in improving adherence to local guidelines promoted the selection of the most cost‐effective treatment in the majority of cases.