The mucosa is part of the first line of immune defense against pathogen exposure in humans and prevents viral and bacterial infection of the soft palate, lungs, uvula, and nasal cavity that comprise the ear-nose-throat (ENT) region. Bactericidal/permeability-increasing fold containing family A, member 1 (BPIFA1) is a secretory protein found in human upper aerodigestive tract mucosa. This innate material is secreted in mucosal fluid or found in submucosal tissue in the human soft palate, lung, uvula, and nasal cavity. BPIFA1 is a critical component of the innate immune response that prevents upper airway diseases. This review will provide a brief introduction of the roles of BPIFA1 in the upper airway (with a focus on the nasal cavity, sinus, and middle ear), specifically its history, identification, distribution in various human tissues, function, and diagnostic value in various upper airway infectious diseases.