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Background: Upper respiratory disease was reported over many seasons in Arabian foals on a single stud farm in the Middle East. Affected foals were noted to have mucopurulent nasal discharge, cough, fever and tachypnea. All affected foals had been empirically treated with a macrolide and rifampicin, by the referring veterinarian without improvement. On endoscopic examination, all affected foals had significant guttural pouch empyema (GPE)., Objectives: (1) To document a previously unreported presentation of guttural pouch empyema (GPE) in a family of juvenile Arabian foals; (2) To document the cytological and microbial composition of the empyema; (3) To identify clinical signs significantly correlated with the presence of GPE, as predictors for the need for guttural pouch (GP) endoscopy; (4) To demonstrate successful resolution of the identified syndrome with mechanical GP lavage and evidence based antimicrobial use, improving antibiotic stewardship and the one-health approach to respiratory disease in this demographic of foals., Methods: Evaluation and scoring of clinical signs, upper airway endoscopy and thoracic ultrasound were performed in 14 affected foals and 10 age-matched controls, followed by comparative tracheal and guttural pouch sputum culture and cytological evaluation. Therapeutic GP lavage was performed and response to therapy monitored., Results: GPE, cranioventrally distributed ultrasonographic lesions and opportunistic pathogen infection suggested a primary lesion of GPE with aspiration of GP discharge into the lungs. GP lavage resolved the empyema and associated clinical signs in all cases., Conclusions: Cytological examination of tracheal and guttural pouch aspirates revealed a neutrophilic exudate with lipid-laden phagocytes, suggestive of engulfed milk. Bacteriology revealed a high prevalence of Streptococcus equi ssp. zooepidemicus admixed with other opportunistic pathogens. Streptococcus equi ssp. equi was not isolated in any case., (© 2023 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)