Recent investigations strongly suggest a role for neurally mediated hypotension (NMH) in the symptomatology of Chronic Fatigue Syndrome (CFS) in adults. Our previous work indicate that autonomic activity measured by heart rate variability (HRV) is abnormal in children with syncope (S) due to NMH during head-up tilt testing (HUT). Therefore, we performed measurements of HRV at HUT in 13 patients aged 11-18 y with CFS defined by CDC guidelines and compared results to 29 S patients. After 30 min supine, patients were tilted to 80° for 30 min or until syncope occurred. Time domain indices included standard deviation (SDNN), root mean square successive differences (RMSSD), percent exceeding 50msec (pNN50). An autoregressive model was used to calculate power spectra. Low frequency power (LFP,.04-.15Hz), high frequency power (HFP,.15-.40Hz), and total power (TP,.01-.40Hz) were compared. HRV data were obtained supine before tilt (baseline), and 5-10 min after HUT. Ten CFS patients fainted (CFS+), and 3 did not (CFS-). HRV indices were not different at baseline for CFS- vs CFS+: SDNN was 52±10 vs 62±7ms, RMSSD was 44±11 vs 51±7ms, pNN50 was 17±7 vs 25±4%, respectively. LFP, HFP, and TP were 442±143, 448±275, and 1287±461ms2 in CFS- vs 589±51, 398±86, and 1686±262 in CFS+. However, these data were strikingly decreased compared to S patients, - 17 fainted during HUT (S+) 12 did not (S-) - in which HRV indices were normal and much higher for S- compared to S+: SDNN was 123±17 vs 78±6ms, RMSSD was 127±23 vs 64±6 ms, pNN50 was 51±6 vs 31±4%, LFP, was 834±133 vs 3433±840, HFP was 3433±840 vs 834±133 and TP was 7062±1500 vs 2855±420 ms. With tilt, SDNN, RMSSD and pNN50 and spectral indices decreased in all groups. We conclude: 1. Chronic Fatigue Syndrome is associated with neurally mediated syncope; 2. All indices of HRV are markedly depressed in CFS patients whether or not syncope is induced during HUT and even when compared with already abnormally low HRV in syncopal patients without CFS. These data suggest severe autonomic impairment in all patients with the Chronic Fatigue Syndrome.