The design, implementation, and assessment of a comprehensive pharmaceutical care program (CPCP) for hepatitis C virus (HCV)-infected patients treated with direct-acting antivirals (DAA) are described. The advent of DAA regimens has caused the evolution of the role of hospital pharmacists, leading to the development of more specialized models of pharmaceutical care. Three clinical pharmacists were incorporated into the pharmacy department of a general tertiary teaching hospital in Madrid, Spain, with the aim of developing and implementing a CPCP for HCV-infected patients. Pharmacists were responsible for proposing standards and local guidelines to physicians, monitoring adherence to guidelines, managing drug interactions and adverse drug events (ADEs), providing patient education, and evaluating health outcomes and costs. Implementation steps included (1) estimation of the healthcare demand and pharmacy resources, (2) definition of the workflow of the CPCP, (3) definition of the treatment care plan, for which tools were developed to support pharmaceutical validation, detection, and management of ADEs and drug–drug interactions, and (4) program assessment in terms of safety and cost-effectiveness. The pharmacists’ interventions performed, severity of errors intercepted, and patients’ satisfaction with the CPCP were also assessed. This CPCP demonstrates that the involvement of the pharmacist throughout the care plan prevents harmful medication errors in this population (0.1 per patient) and prompts significant cost savings (€1.2 million for 1,930 treated patients). The implementation of a CPCP developed by hospital pharmacists for patients treated with DAA for HCV infection is an effective approach for preventing harmful medication errors and improving cost- effectiveness.