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RATIONALE Despite being a hallmark and an independent prognostic factor in several cardiopulmonary diseases, ventilatory efficiency - i.e. minute ventilation/carbon dioxide output relationship (V'E/V'CO2) has never been systematically explored in cystic fibrosis (CF). OBJECTIVE To provide a comprehensive frame of reference regarding measures of ventilatory efficiency in CF adults with normal to moderately impaired lung function and to confirm the hypothesis that V'E/V'CO2 is a sensitive marker of early lung disease. METHODS CF patients were divided into 3 groups according to their spirometry: normal (G1), mild impairment (G2) and moderate impairment (G3) in lung function. All participants underwent incremental cardiopulmonary exercise testing on a cycle-ergometer. Lowest V'E/V'CO2 ratio (nadir) and the slope and the intercept of the linear region of the V'E/V'CO2 relationship were contrasted in a two-center retrospective analysis involving 72 CF patients and 36 healthy controls (HC). RESULTS Compared to HC, CF patients had significantly higher V'E/V'CO2 nadir, slope and intercept (p<0.001, p<0.001 and p=0.049, respectively). Subgroup analysis revealed significant differences in nadir (p=0.001) and slope (p=0.012) values even between HC and G1. Dynamic hyperinflation related negatively with slope (p=0.045) and positively with intercept (p=0.001), whilst no impact on nadir was observed. CONCLUSIONS Ventilatory inefficiency is a clear feature of adults with CF, even among patients with normal spirometry. V'E/V'CO2 nadir seems to be the most reliable metric to describe ventilatory efficiency in CF adults. Further prospective studies are needed to clarify whether V'E/V'CO2 could represent an useful marker in the evaluation of early lung disease in CF.