ABSTRACT INTRODUCTION: Pulmonary exacerbations in Cystic Fibrosis (CF) contribute to the burden of disease with negative impact on quality of life, cost and lung function. Our aim was to evaluate if exacerbations, defined by antibiotic use, were triggered by daily fluctuations in air pollution. METHODS: In a case-crossover analysis we evaluated 215 CF patients and pollution data from 1 January 1998 till 31 December 2010. Exacerbation was defined as the start of intravenous and/or oral antibiotics use in a home or hospital setting. We calculated regional background levels of PM10, ozone and NO2 on the day of the event, and on the 2 days prior to the event at each patient's home address. We matched for day of the week and controlled for temperature on the day of the event and the two preceding days. In the month where antibiotic treatment was started, all days with the same temperature (±2°C) as the event day served as control days, while excluding three days before and after the start of treatment. RESULTS: A total of 215 patients (male 49%, mean age 21 years ± 13) had 2204 treatments (1107 intravenous and 1097 oral antibiotic treatments). Over a period of 12 years, an increase in risk of antibiotic use was associated with increasing concentrations of PM10, NO2 and ozone on the event day and the day before for NO2. A tendency toward significance was seen the day before antibiotic use for PM10 and ozone. Overall, a rise in odds ratio was seen from two days before till the day of the start of antibiotics. CONCLUSION: In patients with CF and exacerbations, ambient concentrations of ozone, PM10 and NO2 play a role in triggering an exacerbation.