Despite being a hallmark and an independent prognostic factor in several cardiopulmonary diseases, ventilatory efficiency—i.e., minute ventilation/carbon dioxide output relationship (V̇e/V̇co₂)—has never been systematically explored in cystic fibrosis (CF). 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 V̇e/V̇co₂is a sensitive marker of early lung disease. CF patients were divided into three 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 V̇e/V̇co₂ratio (nadir) and the slope and the intercept of the linear region of the V̇e/V̇co₂relationship were contrasted in a two-center retrospective analysis, involving 72 CF patients and 36 healthy controls (HC). Compared with HC, CF patients had significantly higher V̇e/V̇co₂nadir, 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), while no impact on nadir was observed. Ventilatory inefficiency is a clear feature of adults with CF, even among patients with normal spirometry. V̇e/V̇co₂nadir seems to be the most reliable metric to describe ventilatory efficiency in CF adults. Further prospective studies are needed to clarify whether V̇e/V̇co₂could represent a useful marker in the evaluation of early lung disease in CF.NEW & NOTEWORTHY This is the first study to investigate ventilatory efficiency in a cohort of adult cystic fibrosis (CF) patients with nonsevere lung disease. The finding of impaired ventilatory efficiency in patients with normal lung function confirms the higher sensitivity of exercise testing in detecting early lung disease compared with spirometry. Dynamic hyperinflation plays a significant role in determining the behavior of V̇e/V̇co₂slope and intercept values with increasing lung function impairment. Apparently free from interference from mechanical constraints, V̇e/V̇co₂nadir seems the most reliable parameter to evaluate ventilatory efficiency in CF adults.