Postural tachycardia syndrome (POTS) is characterized by excessive increases in heart rate (HR) without hypotension during orthostasis. The relationship between the tachycardia and anxiety is uncertain. Therefore, we tested whether the HR response to orthostatic stress in POTS is primarily related to psychological factors. POTS patients (n=14) and healthy controls (n=10) underwent graded venous pooling with lower body negative pressure (LBNP) to -40 mmHg while wearing deflated antishock trousers. "Sham" venous pooling was performed by: 1) trouser inflation to 5 mmHg during LBNP and 2) vacuum pump activation without LBNP. HR responses to mental stress were also measured in both groups, and a questionnaire was used to measure psychological parameters. During LBNP, HR in POTS patients increased 39±5 beats/min vs. 19±3 beats/min in control subjects at -40 mmHg (P<0.01). LBNP with trouser inflation markedly blunted the HR responses in the patients (9±2 beats/min) and controls (2±1 beats/min), and there was no HR increase during vacuum application without LBNP in either group. HR responses during mental stress were not different in the patients and controls (18±2 vs 19±1 beats/min; P>0.6). Anxiety, somatic vigilance, and catastrophic cognitions were significantly higher in the patients (P<0.05), but not related to the HR responses during LBNP or mental stress (P>0.1). These results suggest that the HR response to orthostatic stress in POTS patients is not caused by anxiety, but is a physiological response that maintains arterial pressure during venous pooling.