Background: Among patients with cystic fibrosis (CF), methicillin-resistant Staphylococcus aureus (MRSA)-associated acute pulmonary exacerbations (APEs) are increasing in prevalence and can cause rapid declines in lung function and mortality. Limited data exist on the preferred treatment of MRSA-associated APEs, with vancomycin often considered first-line. Given the potential toxicities and intolerances associated with vancomycin, evaluating alternative therapies such as doxycycline is warranted. Methods: This evaluation is a multicenter retrospective cohort study of adult and pediatric patients with a CF diagnosis who received greater than 48 hrs of either vancomycin or doxycycline to treat MRSA-associated APEs. The primary outcome was the incidence of patients with a return to ≥90% of baseline forced expiratory volume in the first second (FEV 1). Results: 229 patient encounters were screened of which 89 met inclusion criteria (n = 26, vancomycin; n = 63, doxycycline). There were no differences between vancomycin and doxycycline for the primary outcome: 18/26, (69.2%) in the vancomycin group versus 51/63 (81.0%) in the doxycycline group (p = 0.23). Conclusions: Doxycycline was comparable to vancomycin in the rate of return to ≥90% of baseline FEV 1 and for all secondary efficacy outcomes. While the results of this study are limited by the small sample size, retrospective design, and lack of power, the findings suggest doxycycline may be a reasonable alternative to vancomycin for MRSA-associated APEs, particularly in patients who may not tolerate vancomycin or who require concomitant nephrotoxins such as intravenous aminoglycosides.