Upper respiratory tract infections are responsible for millions of physician visits in the United States annually. Although viruses cause most acute upper respiratory tract infections, studies show that many infections are unnecessarily treated with antibiotics. Because inappropriate antibiotic use results in adverse events, contributes to antibiotic resistance, and adds unnecessary costs, family physicians must take an evidence -based, judicious approach to the use of antibiotics in patients with upper respiratory tract infections. Antibiotics should not be used for the common cold, influenza, COVID-19, or laryngitis. Evidence supports antibiotic use in most cases of acute otitis media, group A beta hemolytic streptococcal pharyngitis, and epiglottitis and in a limited percentage of acute rhinosinusitis cases. Several evidence -based strategies have been identified to improve the appropriateness of antibiotic prescribing for acute upper respiratory tract infections. (Am Fam Physician. 2022;106(6):628-636. Copyright (c) 2022 American Academy of Family Physicians.)