Health care–associated infections (HAIs) remain the most common adverse event affecting patients while hospitalized and after discharge. However, applying patient safety techniques as well as traditional infection control methods has resulted in significant successes in curbing these infections. This practice guideline, developed by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America, summarizes preventive interventions and implementation strategies for prevention of the four most common HAIs (catheter-related bloodstream infection, ventilator-associated pneumonia, catheter-associated urinary tract infection, and surgical site infection). Evidence-based recommendations are also provided for limiting the transmission of methicillin-resistant Staphylococcus aureus and preventing Clostridium difficile infections. More recent recommendations are currently in development.