Adenosine triphosphate (ATP) released from circulating erythrocytes is a potential signal regulating muscle blood flow during exercise (exercise hyperemia) and intravascular ATP appears to blunt sympathetic vasoconstriction during exercise. Erythrocytes from patients with cystic fibrosis (CF) do not release ATP. The goal of the present study was to determine whether increases in forearm blood flow (FBF) during exercise are blunted in patients with CF and whether patients with CF exhibit greater vasoconstrictor responsiveness during exercise. Nine control subjects and 10 patients with CF, who were free of any other disease complications (oxygen saturation ~96%), performed incremental rhythmic forearm exercise at 5, 10, and 15% of maximum handgrip strength for 21 minutes (7 minutes at each workload). We used a cold pressor test to evoke sympathetic vasoconstriction under resting conditions and at each exercise workload. As a control, subjects performed a second exercise bout without the cold pressor test. Continuous brachial artery blood velocity was monitored beat-to-beat and vessel diameter was assessed by Doppler ultrasound. Artery diameter measurements, as well as blood pressure, heart rate, and oxygen saturation were obtained at steady state exercise and at 1 min into the cold pressor stimulus. Blood pressure and heart rate responses to the forearm exercise and each cold pressor test were similar in both groups (P>0.05). Contrary to our hypothesis, both FBF (P = 0.91) and forearm vascular conductance (FVC, P = 0.82) were similar at rest and at each level of exercise between patients with CF and controls. Additionally, there was no difference in the degree of sympathetic vasoconstriction between groups at rest and at each level of exercise (P = 0.22). Our results suggest that ATP released from the deformation of erythrocytes is not an obligatory signal for exercise hyperemia in human skeletal muscle.