Upright hyperventilation occurs in approximately 25% of our patients with postural tachycardia syndrome (POTS). Poikilocapnic hyperventilation alone causes tachycardia. Here we examined changes in respiration and hemodynamics comprising cardiac output (CO), systemic vascular resistance (SVR) and blood pressure (BP) measured during head-up tilt (HUT) in 3 groups: patients with POTS and hyperventilation (POTS-HV), patients with Panic Disorder who hyperventilate (Panic), and healthy controls performing voluntary upright hyperpnea (Voluntary-HV). Though all were comparably tachycardic during hyperventilation, POTS-HV manifested hyperpnea, decreased CO, increased SVR and increased BP during HUT; Panic patients showed both hyperpnea and tachypnea, increased CO and increased SVR as BP increased during HUT; and Voluntary-HV were hyperneic by design and had increased CO, decreased SVR, and decreased BP during upright hyperventilation. Mechanisms of hyperventilation and hemodynamic changes differed among POTS-HV, Panic and Voluntary-HV subjects. We hypothesize that the hyperventilation in POTS is caused by a mechanism involving peripheral chemoreflex sensitization by intermittent ischemic hypoxia.