Rationale: The prevalence in cystic fibrosis (CF) of respiratory cultures with methicillin-resistant Staphylococcus aureus (MRSA) has dramatically increased over the last ten years, but the effect of MRSA on FEV₁ decline in CF is unknown. Objective: To determine the association between MRSA respiratory infection and FEV₁ decline in children and adults with CF. Methods: Ten-year cohort study using the CF Foundation patient registry from 1996-2005. We studied individuals who developed new MRSA respiratory tract infection. Repeated measures regression was used to assess the association between MRSA and FEV₁ decline, adjusted for confounders, in individuals aged 8-21 and adults (aged 22-45). Two different statistical models were used to assess robustness of results. Measurements and Main Results: The study cohort included 17,357 patients with an average follow-up of 5.3 years. During the study period 1732 individuals developed new persistent MRSA infection (3 MRSA cultures; average 6.8 positive cultures) and were subsequently followed for an average of 3.5 years. Even after adjustment for confounders, rate of FEV₁ decline in individuals aged 8-21 with persistent MRSA was more rapid in both statistical models. Their average FEV₁ decline of 2.06% predicted/year was 43% more rapid than the 1.44% predicted/year in those without MRSA (difference -0.62% predicted/year, 95% CI -0.70 to -0.54; p<0.001). Effect of MRSA on FEV₁ decline in adults was not clinically significant. Conclusions: Persistent infection with MRSA in individuals with CF between the ages of 8-21 is associated with a more rapid rate of decline in lung function.