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Cystic fibrosis (CF) is characterized by chronic respiratory infections which progressively decrease lung function over time. Affected individuals experience episodes of intensified respiratory symptoms called pulmonary exacerbations (PEx), which in turn accelerate pulmonary function decline and decrease survival rate. An overarching challenge is that there is no standard classification for PEx, which results in treatments that are heterogeneous. Improving PEx classification and management is a significant research priority for people with CF. Previous studies have shown volatile organic compounds (VOCs) in exhaled breath can be used as biomarkers because they are products of metabolic pathways dysregulated by different diseases. To provide insights on PEx classification and other CF clinical factors, exhaled breath samples were collected from 18 subjects with CF, with some experiencing PEx and others serving as a baseline. Exhaled breath was collected in Tedlar bags during tidal breathing and cryotransferred to headspace vials for VOC analysis by solid phase microextraction coupled to gas chromatography–mass spectrometry. Statistical significance testing between quantitative and categorical clinical variables displayed percent-predicted forced expiratory volume in one second (FEV1pp) was decreased in subjects experiencing PEx. VOCs correlating with other clinical variables (body mass index, age, use of highly effective modulator treatment (HEMT), and the need for inhaled tobramycin) were also explored. Two volatile aldehydes (octanal and nonanal) were upregulated in patients not taking the HEMT. VOCs correlating to potential confounding variables were removed and then analyzed by regression for significant correlations with FEV1pp measurements. Interestingly, the VOC with the highest correlation with FEV1pp (3,7-dimethyldecane) also gave the lowestp-value when comparing subjects at baseline and during PEx. Other VOCs that were differentially expressed due to PEx that were identified in this study include durene, 2,4,4-trimethyl-1,3-pentanediol 1-isobutyrate and 5-methyltridecane. Receiver operator characteristic curves were developed and showed 3,7-dimethyldecane had higher ability to classify PEx (area under the curve (AUC) = 0.91) relative to FEV1pp values at collection (AUC = 0.83). However, normalized ΔFEV1pp values had the highest capability to distinguish PEx (AUC = 0.93). These results show that VOCs in exhaled breath may be a rich source of biomarkers for various clinical traits of CF, including PEx, that should be explored in larger sample cohorts and validation studies.