The prevalence of methicillin resistant Staphylococcus aureus (MRSA) infections is increasing in both the general population and cystic fibrosis (CF) patients. We hypothesized that MRSA infection of the conductive airways as seen in CF would be associated with more severe disease than that seen with methicillin sensitive S. aureus (MSSA). To test this hypothesis, we used data from the Epidemiologic Study of Cystic Fibrosis (ESCF), a large observational study of CF patients in North America, to compare CF patients with MRSA in their respiratory tract cultures to those with MSSA. During a 1-year time period from January 1, 2001 to December 31, 2001, data from 20,451 patients were collected by the ESCF, and 1,834 (7.5%) patients had respiratory tract cultures that were positive for S. aureus only. Compared to patients with MSSA only, patients with MRSA only had significantly more airflow obstruction, as measured by forced expiratory volume in 1 sec (FEV1). The mean FEV1 for patients 6–17 years old with MRSA was 80.7% predicted compared to 89.4% in the MSSA group (P < 0.001). The likelihood of hospitalization and treatment with oral, inhaled, and intravenous antibiotics were all significantly increased in patients with MRSA compared to those with MSSA. Similar results were seen in patients ≥18 years old. The results of our study highlight the growing clinical impact of MRSA infections in CF patients. Pediatr Pulmonol. 2007; 42:513–518. © 2007 Wiley-Liss, Inc.