These guidelines form part of efforts to institutionalize the prevention and containment of antimicrobial resistance (AMR) in health care facilities in South Africa, as outlined in the Antimicrobial Resistance Strategic Framework and Implementation Plan. The focus of these guidelines is on two interrelated aspects of prevention of healthcare associated infections (HAIs) and their spread; and the application of antimicrobial stewardship (AMS) practices at hospital level. They aim to serve as a practical, step-by-step or ‘how-to’ guide, addressing the infection prevention and AMS components of a robust response in a hospital. They draw on evidence from various international guidance documents and standards for interventions that have been shown to be successful in infection prevention and AMS programs.