Purpose To assess the effects of two different body positions on the cardiovascular autonomic profile during a single bout of exercise in patients with postural orthostatic tachycardia syndrome (POTS). Methods Thirteen patients with POTS and thirteen healthy controls (C) participated in the study. ECG, respiration, beat-by-beat arterial pressure and O2 consumption (VO2) were continuously recorded while on a cycle ergometer in supine and upright positions, before and during exercise (6 min, 50 Watts). Spectral analysis of RR intervals and systolic arterial pressure (SAP) variability provided indexes of cardiac sympathovagal interaction (LF/HF ratio), cardiac vagal modulation (HFRR, high-frequency component of RR variability, ~ 0.25 Hz), sympathetic vasomotor control (LFSAP, low-frequency component of SAP variability, 0.1 Hz) and baroreflex sensitivity (BRS, αLF). Results While supine, patients with POTS showed lower HFRR and αLF, greater heart rate (HR), LF/HF and LFSAP, compared with C, suggesting cardiovascular sympathetic over-activity and reduced BRS. While sitting upright, POTS showed greater HR and reduced HFRR and αLF compared with C. During supine exercise, SAP, HR, LF/HF increased and HFRR and αLF decreased similarly in POTS and C. In POTS, upright sitting exercise was associated with slightly higher vo2 , a greater increase in HR whereas LFSAP was lower than in C. Conclusion Upright exercise was associated with excessive enhancement of HR and a blunted increase of the sympathetic vasomotor control in POTS. Conversely, supine exercise-induced hemodynamic and autonomic changes similar in POTS and C, thus making supine exercise potentially more suitable for physical rehabilitation in POTS.