Previous studies comparing cardiac output (Q) and stroke volume (SV) between cystic fibrosis (CF) patients and control subjects have shown conflicting results: some found lower SV in CF patients with severe airflow limitation, and others showed no difference between CF and control subjects. Methodologic problems could explain these discrepant findings. The aim of this study was to better characterize Q and SV with exercise in CF patients with mild as well as severe airflow obstruction. Subjects included 18 CF patients with FEV1 ranging from 28 to 80% of predicted without pulmonary hypertension, and 16 matched control subjects. Cardiac output was measured at three levels of upright cycle exercise using the indirect Fick (CO2) method with blood gas sampling. Q on exercise was similar among control and CF subjects. SV was lower in CF patients, particularly those with FEV1 < or = 55% predicted, than in control subjects. Stepwise regression of SV on height, percent ideal body weight, and FEV1 showed a significant effect of relative underweight on SV. Despite this, well-nourished patients with FEV1 56 to 80% of predicted also had lower SV. As these findings were consistent across the range of severity of lung disease and age, even in the absence of malnutrition, they imply that another mechanism accounts for SV limitation during exercise in CF.