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 during exercise are blunted in CF patients and whether CF patients exhibit greater vasoconstrictor responsiveness during exercise. Nine control subjects and 10 CF patients who were free of other disease complications (approximately 96% O2 saturation) performed incremental rhythmic forearm exercise at 5, 10, and 15% of maximum handgrip strength for 21 min (7 min 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, as well as blood pressure, heart rate, and O2 saturation, was measured 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, forearm blood flow (P = 0.91) and forearm vascular conductance (P = 0.82) were similar at rest and at each level of exercise between CF patients 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.