Background: Macrolide antibiotics are used as firt-line therapy for the treatment of respiratory tract infections. The recent emergence of macrolide-resistant pathogens is a major concern. Objective: This study quantifies the frequency of macrolide treatment failure in respiratory infections and examines its impact on health care use. Methods: Patients with respiratory infections treated with macrolides in outpatient clinics from January to December 2002 were identified from a health insurance claims database. Macrolide treatment failure was defined as the receipt of a second antibiotic, different from the first, within 4 weeks after the initial macrolide. The end points were numbers of hospitalizations and emergency department and office visits within 1 month after the initial macrolide. We examined diagnostic codes on claim forms for posttreatment hospitalizations and visits to identify those most likely to be related to treatment failure as opposed to other causes. Utilization data were analyzed by Poisson regression to control for confounding variables. Results: The patients were divided into acute sinusitis (n = 111,135), acute bronchitis (n = 157,360), and community-acquired pneumonia (n = 36,212). Of these respective groups, 11,285 (10.2%), 15,498 (9.9%), and 4144 (11.4%) received a second antibiotic within 4 weeks. This subgroup with macrolide treatment failure was older, included more women, and had used more medical care before the index visit compared with patients with treatment success. After adjustment for age, sex, and previous health care use, patients experiencing treatment failure were more likely to be admitted to the hospital or to use emergency department or outpatient care after the index visit. This association was strongest for admissions and visits pertaining to the care of respiratory infections. Conclusions: By our definition, about 10% of patients with respiratory infections who were treated with macrolide antibiotics experienced treatment failure within 4 weeks. Macrolide treatment failure was associated with increased health care utilization.