Aims To determine whether central serotoninergic system activity is impaired by orthostatic challenge in patients with neurocardiogenic syncope (NCS). Methods and results Thirty-five [mean age: 24 (SD): 6 years] patients with a clinical history of NCS and positive head-up tilt test and 35 age-matched healthy volunteers (CON=25±5 years) with negative response were studied. Overnight dexamethasone suppression test (DST) (1.5 mg given at 11 p.m.) was performed to assess the sensitivity of the hypothalamic-pituitary-adrenal axis by measuring next day cortisol (µg/dL) at 8 a.m. and 4 p.m. Cardiac autonomic function, cortisol, and prolactin (ng/dL) were also determined at baseline supine (BAS) and after 5, 10, and 15 min of orthostatic stress (OS) at 60°. No significant differences were observed in cortisol plasma levels after the DST: CON=0.6±0.6 µg/dL vs. NCS=0.6±0.5; P =0.7. Cardiac autonomic function, cortisol, and prolactin responses were similar in both study groups (CON vs. NCS; P >0.05) during BAS: cortisol=8.6±4 vs.8.7±4 µg/dL and prolactin=16.8±9 vs. 16.8±9 ng/dL; OS-5: cortisol=8.7±5 vs. 8.5±4 µg/dL and prolactin=16.9±9 vs. 15.8±9 ng/dL; OS-10: cortisol=8.5±5 vs. 8.1±3 µg/dL; prolactin=16.2±9 vs. 15.8±9 ng/dL, and OS-15: cortisol=9.0±5 vs. 8.4±4 µg/dL; prolactin=17.1±9 vs. 15.5±9 ng/dL. Conclusion Central serotoninergic response during orthostatic challenge was not impaired in patients with recurrent NCS. These findings suggest that the activation of the hypothalamic-pituitary-adrenal axis is not altered in patients with recurrent NCS.