The physiological challenge of standing upright is evidenced by temporary symptoms of light-headedness, dizziness, and nausea. It is not known, however, if initial orthostatic hypotension (IOH) and related symptoms associated with standing are related to the occurrence of syncope. Since IOH reflects immediate and temporary adjustments compared with the sustained adjustments during orthostatic stress, we anticipated that the severity of IOH would be unrelated to syncope. Following a standardized period of supine rest, healthy volunteers [n=46; 25+/-5 yr old (mean+/-SD)] were instructed to stand upright for 3 min, followed by 60 degrees head-up tilt with lower-body negative pressure in 5-min increments of -10 mmHg, until presyncope. Beat-to-beat blood pressure (radial arterial or Finometer), middle cerebral artery blood velocity (MCAv), end-tidal PCO2, and cerebral oxygenation (near-infrared spectroscopy) were recorded continuously. At presyncope, although the reductions in mean arterial pressure, MCAv, and cerebral oxygenation were similar to those during IOH (40+/-11 vs. 43+/-12%; 36+/-18 vs. 35+/-13%; and 6+/-5 vs. 4+/-2%, respectively), the reduction in end-tidal CO2 was greater (-7+/-6 vs. -4+/-3 mmHg) and was related to the decline in MCAv (R2=0.4; P<0.05). While MCAv pulsatility was elevated with IOH, it was reduced at presyncope (P<0.05). The cardiorespiratory and cerebrovascular changes during IOH were unrelated to those at presyncope, and interestingly, there was no relationship between the hemodynamic changes and the incidence of subjective symptoms in either scenario. During IOH, the transient nature of physiological changes can be well tolerated; however, potentially mediated by a reduced MCAv pulsatility and greater degree of hypocapnic-induced cerebral vasoconstriction, when comparable changes are sustained, the development of syncope is imminent.