BACKGROUND: Chronic nausea in pediatrics is a debilitating condition with unclear etiology. We aimed to define hemodynamic and neurohumoral characteristics of chronic nausea associated with orthostatic intolerance in order to improve identification and elucidate mechanism. METHODS: Children (10-18 years) meeting Rome III criteria for functional dyspepsia with nausea and symptoms of orthostatic intolerance (OI) completed a Nausea Profile Questionnaire followed by prolonged (45 minutes rather than the traditional 10 minutes) head-upright tilt (HUT) (70 degrees tilt up) test. Circulating catecholamines, vasopressin, aldosterone, renin, and angiotensins were measured supine and after 15 minutes into HUT. Beat-to-beat heart rate and blood pressure were continuously recorded to calculate their variability and baroreflex sensitivity. KEY RESULTS: Within 10 and 45 minutes of HUT, 46% and 85% of subjects, respectively, had an abnormal tilt test (orthostatic hypotension, postural orthostatic tachycardia, or syncope). At 15 and 45 minutes of HUT, nausea was elicited in 42% and 65% of subjects respectively. Higher Nausea Profile Questionnaire scores correlated with positive HUT testing at 10 minutes (P = 0.004) and baroreflex sensitivity at 15 minutes (P = 0.01). Plasma vasopressin rose 33-fold in subjects with HUT-induced nausea compared to twofold in those who did not experience HUT-induced nausea (P < 0.01). CONCLUSIONS AND INFERENCES: In children with chronic nausea and OI, longer duration HUT elicited higher frequency of abnormal tilt testing and orthostatic-induced nausea. The Nausea Profile Questionnaire predicted the orthostatic response to tilt testing. Exaggerated vasopressin release differentiated patients with HUT-induced nausea (vs those without nausea), suggesting a possible mechanism for chronic nausea in childhood.