Postural tachycardia syndrome (POTS) is characterized by excessive tachycardia without hypotension during orthostasis. Most POTS patients also report exercise intolerance. To assess cardiovascular regulation during exercise in POTS, patients (n=13) and healthy controls (n=10) performed graded cycle exercise at 25, 50, and 75W in both supine and upright positions while arterial pressure (arterial catheter), heart rate (HR, ECG), and cardiac output (open-circuit acetylene breathing) were measured. In both positions, mean arterial pressure, cardiac output, and total peripheral resistance at rest and during exercise were similar in patients and controls (P>0.05). However, supine stroke volume (SV) tended to be lower in the patients than controls at rest (99±5 vs 110±9 ml) and during 75W exercise (97±5 vs 111±7 ml) (P=0.07), and HR was higher in the patients than controls at rest (76±3 vs 62±4 beats/min) and during 75W exercise (127±3 vs 114±5 beats/min) (both P<0.01). Upright SV was significantly lower in the patients than controls at rest (57±3 vs 81±6 ml) and during 75W exercise (70±4 vs 94±6 ml) (both P<0.01), and HR was much higher in the patients than controls at rest (103±3 vs 81±4 beats/min) and during 75W exercise (164±3 vs 131±7 beats/min) (both P<0.001). The change (upright-supine) in SV was inversely correlated with the change in HR for all participants at rest (R²=0.32), at 25W (R²=0.49), 50W (R²=0.60), and 75W (R²=0.32) (P<0.01). These results suggest that greater elevation in HR in POTS patients during exercise, especially while upright, was secondary to reduced SV and associated with exercise intolerance.