Background: Several studies have described a clinical benefi t of macrolides due to their immunomodulatory properties in various respiratory diseases. We aimed to assess the effect of macrolide therapy on mortality in patients hospitalized for Pseudomonas aeruginosa community-acquired pneumonia (CAP). Methods: We performed a retrospective population-based study of > 150 hospitals in the US Veterans Health Administration. Patients were included if they had a diagnosis of CAP and P aeruginosa was identifi ed as the causative pathogen. Patients with health-care-associated pneumonia and immunosuppression were excluded. Macrolide therapy was considered when administered within the fi rst 48 h of admission. Univariate and multivariable analyses were performed using 30-day mortality as the dependent measure. Results: We included 402 patients with P aeruginosa CAP, of whom 171 (42.5%) received a macrolide during the fi rst 48 h of admission. These patients were older and white. Macrolide use was not associated with lower 30-day mortality (hazard ratio, 1.14; 95% CI, 0.70-1.83; P 5 .5). In addition, patients treated with macrolides had no differences in ICU admission, use of mechanical ventilation, use of vasopressors, and length of stay (LOS) compared with patients not treated with macrolides. A subgroup analysis among patients with P aeruginosa CAP in the ICU showed no differences in baseline characteristics and outcomes. Conclusions: Macrolide therapy in the fi rst 48 h of admission is not associated with decreased 30-day mortality, ICU admission, need for mechanical ventilation, and LOS in hospitalized patients with P aeruginosa CAP. Larger cohort studies should address the benefi t of macrolides as immunomodulators in patients with P aeruginosa CAP. © 2014 American College of Chest Physicians.