Enclosed-space smoke inhalation is the fifth most common cause of all unintentional injury deaths in the United States. Increasingly, cyanide has been recognized as a significant toxicant in many cases of smoke inhalation. However, it cannot be emergently verified. Failure to recognize the possibility of cyanide toxicity may result in inadequate treatment. Findings suggestive cyanide toxicity include: (1) a history of an enclosed-space fire scene in which smoke inhalation was likely; (2) the presence of oropharyngeal soot or carbonaceous expectorations; (3) any alteration of the level of consciousness, and particularly, otherwise inexplicable hypotension (systolic blood pressure ≤90 mmHg in adults). Prehospital studies have demonstrated the feasibility and safety of empiric treatment with hydroxocobalamin for patients with suspected smoke inhalation cyanide toxicity. Although United States Food and Drug Administration (FDA)-approved since 2006, the lack of efficacy data has stymied the routine use of this potentially lifesaving antidote. Based on a literature review and on-site observation of the Paris Fire Brigade, emergency management protocols to guide empiric and early hydroxocobalamin administration in smoke inhalation victims with high-risk presentations are proposed.