OBJECTIVE: To provide the first description of intratympanic bacteriophage therapy for chronic mastoiditis from multidrug-resistant Pseudomonas aeruginosa in the United States. PATIENTS: A 47-year-old woman with chronic mastoiditis in the setting of ciliary dysfunction from cystic fibrosis and immunosuppression from lung transplantation. INTERVENTIONS: Ten concurrent parenteral and intratympanic doses of two custom phages targeting P. aeruginosa followed by IV antibiotic therapy. MAIN OUTCOME MEASURES: Resolution of infection confirmed by symptomatology, cultures, and imaging. RESULTS: At 5 months after phage treatment, the patient reported resolution of otorrhea, headaches, and hearing impairment. Subsequent cultures showed no growth. CONCLUSIONS: Bacteriophages can enhance antibiotic activity in cases of drug-resistant chronic mastoiditis.