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Perioral hematomas can lead to acute airway compromise and can present significant challenges in both direct and indirect approaches to airway instrumentation. In patients with normal cell counts and routine coagulation tests, spontaneous hematomas are rare, but when encountered, they elicit a limited differential diagnosis that includes von Willebrand factor deficiency, platelet dysfunction, and the acquired factor XIII (FXIII) deficiency. Although spontaneous hematoma formation resulting from FXIII inhibition has been reported, we describe what may be the first reported case of FXIII inhibitor-related hematoma leading to acute airway compromise. Successful management of this patient required multidisciplinary cooperation among anesthesiologists, intensivists, otolaryngologists, and hematologists.