This chapter addresses how heating, ventilation, and air-conditioning (HVAC) mechanical systems are used in healthcare facilities to prevent and control infections. HVAC systems are designed to support asepsis in the healthcare environment for patient care, including in critical areas such as operating rooms (ORs) where invasive procedures occur. For example, HVAC systems support asepsis by providing clean, filtered, and conditioned air in the OR to protect the surgical site, as well as in sterile processing, assembly, and storage areas for surgical instruments within the sterile processing department. HVAC systems can also provide odor control; effectively remove contaminants (chemical, physical, and biological) from indoor air; control indoor temperature, humidity, and air exchanges; and maintain pressure relationships required for specific spaces and room types. Problems with HVAC systems—including poor design and installation, system performance problems, and inadequate maintenance—increase the risk for infections from the airborne transmission of microorganisms such as Mycobacterium tuberculosis, measles, varicella zoster virus, and Aspergillus spp., as well as newly emerging high consequence pathogens.. The COVID-19 pandemic triggered reexamination of the movement of pathogens through air and has led to an increased emphasis on the use of engineering controls to protect building occupants from exposure to possible pathogens.