Copyright © 2014 by the American Thoracic Society. Rationale: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation. Objectives: To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers. Methods: We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, b-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P , 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m2; P , 0.001). Sweat chloride decreased from baseline to 6 months (mean change, 253.8 mmol/L; 95% confidence interval, 257.7 to 249.9; P , 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P , 0.001) and Pseudomonas aeruginosa burden (P , 0.01). Significant improvements in mucociliary clearance (P,0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor. Conclusions: Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.