Information concerning the impact of environmental factors on cystic fibrosis (CF) is limited. We conducted a cohort study to assess the impact of air pollutants in CF. The study included patients over the age of 6 years enrolled in the Cystic Fibrosis Foundation National Patient Registry in 1999 and 2000. Exposure was assessed by linking air pollution values from the Aerometric Information Retrieval System with the patients' home zip code. After adjusting for confounders, a 10 μg/m³ rise in particulate matter (both with a median aerodynamic diameter of 10 μm (PM₁₀) or less and with an aerodynamic diameter of 2.5 μm or less (PM_2.5) was associated with an 8% (95% confidence interval [CI], 2–15%) and 21% (95% CI, 7–33%) increase in the odds of two or more exacerbations, respectively; a 10-ppb rise in ozone was associated with a 10% (95% CI, 3–17%) increase in odds of two or more exacerbations. For every increase in PM_2.5 of 10 μg/m³, there was an associated fall in FEV₁ of 24 ml (7–40) (95% CI) after adjusting for confounders. PM_2.5's association with mortality did not achieve statistical significance (adjusted RR = 1.32 per 10 μg/m³ 0.91–1.93; 95% CI). Annual average exposures to particulate air pollution was associated with an increased risk of pulmonary exacerbations and a decline in lung function, suggesting a role of environmental exposures on prognosis in CF.