Previous work has shown that impaired exercise tolerance in children with cystic fibrosis (C.F.) is related to the severity of airway obstruction without elucidating the possible roles of hypoxia or malnutrition. It has been suggested that poor nutrition leads to abnormalities in serum fatty acids composition, which may lead to tissue hypoxia. We investigated the roles of hypoxia, pulmonary mechanics, nutritional status, and serum fatty acid composition in limiting exercise tolerance in C.F. In 20 children with C.F., exercise tolerance, while breathing air and while breathing oxygen, was evaluated on a cycle ergometer and compared to pulmonary function tests, anthropometric data, serum lipid compostition, and clinical condition. The mean percent work expected from height (Wmax) was 75, and was unchanged by O2. Wmax correlated significantly with the degree of respiratory impairement, the discrepancy between height and weight, and the clinical score but not serum fatty acid composition. Where measured, no child at any time had an elevated end tidal CO2(PetCO2). We conclude that nutritional status and airway obstruction are closely correlated with exercise tolerance in C.F. and that, unlike the case in adults with chronic obstructive pulmonary disease, exercise-limiting dyspnea occurs in the presence of a normal PetCO2.