This study investigated whether Elexacaftor-Tezacaftor-Ivacaftor (Kaftrio ^®), a cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator, could improve exercise capacity in adolescents with CF. After six weeks treatment, Kaftrio ^® improved both maximal and submaximal indices of aerobic fitness. Improvements were independent of changes in ventilatory function during exercise and physical activity. Interestingly, pulmonary oxygen uptake per unit of power output was higher in two, out of three, cases who presented with more severe CF lung disease. These findings suggest improved O ₂ extraction and/or consumption in the exercising muscle and demonstrate, for the first time, that short-term treatment with Kaftrio ^® might improve aerobic fitness in people with CF, especially in those with more severe lung disease and deconditioning.