This study examined the cardiovascular response to orthostatic challenge, and incidence and mechanisms of neurally mediated hypotension in chronic fatigue syndrome (CFS) during a head-up tilt test. Stoke volume was obtained by a thoracic impedance cardiograph, and continuous heart rate and blood pressure were recorded during a 45-min 70° head-up tilt test. Thirty-nine CFS patients and 31 healthy physically inactive control subjects were studied. A positive tilt, i.e. a drop in systolic blood pressure openface> 25 mmHg, no concurrent increase in heart rate and/or development of presyncopal symptoms, was seen in 11 CFS patients and 12 control subjects (P>0·05). During baseline and the first 5 min of head-up tilt, CFS patients had higher heart rate and smaller pulsatile-systolic area than control subjects (P<0·05). Among subjects who completed the test, those with CFS had higher heart rate and smaller stroke volume (P<0·05) than corresponding control subjects. When comparing those who had a positive test outcome in each group, CFS patients had higher heart rates and lower pulse pressure and pulsatile-systolic areas during the last 4 min before being returned to supine (P<0·05). These data show that there are baseline differences in the cardiovascular profiles of CFS patients when compared with control subjects and that this profile is maintained during head-up tilt. However, the frequency of positive tilts and the haemodynamic adjustments made to this orthostatic challenge are not different between groups.