This study aimed to define cardiovascular and heart rate variability (HRV) changes following head-up tilt (HUT) in children/adolescents with chronic fatigue syndrome (CFS) in comparison to age-and gender-matched controls. Twenty-six children/ adolescents with CFS (11-19 y) and controls underwent 70-degree HUT for a maximum of 30 min, but returned to horizontal earlier at the participant's request with symptoms of orthostatic intolerance (OI) that included lightheadedness. Using electrocardiography and beat-beat finger blood pressure, a positive tilt was defined as OI with 1) neurally mediated hypotension (NMH); bradycardia (HR Ͻ75% of baseline), and hypotension [systolic pressure (SysP) drops Ͼ25 mm Hg)] or 2) postural orthostatic tachycardia syndrome (POTS); HR increase Ͼ30 bpm, or HR Ͼ120 bpm (with/without hypotension). Thirteen CFS and five controls exhibited OI generating a sensitivity and specificity for HUT of 50.0% and 80.8%, respectively. POTS without hypotension occurred in seven CFS subjects but no controls. POTS with hypotension and NMH occurred in both. Predominant sympathetic components to HRV on HUT were measured in CFS tilt-positive subjects. In conclusion, CFS subjects were more susceptible to OI than controls, the cardiovascular response predominantly manifest as POTS without hypotension, a response unique to CFS suggesting further investigation is warranted with respect to the pathophysiologic mechanisms involved. (Pediatr Res 63: 196-202, 2008)