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High-consequence pathogens create a unique problem. To provide effective treatment for infected patients while providing safety for the community, a series of 10 high-level isolation units have been created across the country; they are known as Regional Ebola and Special Pathogen Treatment Centers (RESPTCs). The activation of a high-level isolation unit is a highly resource-intensive activity, with effects that ripple across the healthcare system. The incident command system (ICS), a standard tool for command, control, and coordination in domestic emergencies, is a command structure that may be useful in a biocontainment event. A version of this system, the hospital emergency incident command system, provides an adaptable all-hazards approach in healthcare delivery systems. Here we describe its utility in an operational response to safely care for a patient(s) infected with a high-consequence pathogen on a high-level isolation unit. The Johns Hopkins Hospital created a high-level isolation unit to manage the comprehensive and complex needs of patients with high-consequence infectious diseases, including Ebola virus disease. The unique challenges of and opportunities for providing care in this high-level isolation unit led the authors to modify the hospital incident command system model for use during activation. This system has been tested and refined during full-scale functional and tabletop exercises. Lessons learned from the after-action reviews of these exercises led to optimization of the structure and implementation of ICS on the biocontainment unit, including improved job action sheets, designation of physical location of roles, and communication approaches. Overall, the adaptation of ICS for use in the high-level isolation unit setting may be an effective approach to emergency management during an activation.