Epidemiological data indicate that the risk of neurally mediated syncope is substantially higher in the morning. Syncope is precipitated by cerebral hypoperfusion, yet no chronobiological experiment has been undertaken to examine whether the major circulatory factors, which influence perfusion, show diurnal variation during a controlled orthostatic challenge. Therefore, we examined the diurnal variation in orthostatic tolerance and circulatory function measured at baseline and at presyncope. In a repeated-measures experiment, conducted at 0600 and 1600, 17 normotensive volunteers, aged 26 +/- 4 yr (mean +/- SD), rested supine at baseline and then underwent a 60 degrees head-up tilt with 5-min incremental stages of lower body negative pressure until standardized symptoms of presyncope were apparent. Pretest hydration status was similar at both times of day. Continuous beat-to-beat measurements of cerebral blood flow velocity, blood pressure, heart rate, stroke volume, cardiac output, and end-tidal Pco(2) were obtained. At baseline, mean cerebral blood flow velocity was 9 +/- 2 cm/s (15%) lower in the morning than the afternoon (P < 0.0001). The mean time to presyncope was shorter in the morning than in the afternoon (27.2 +/- 10.5 min vs. 33.1 +/- 7.9 min; 95% CI: 0.4 to 11.4 min, P = 0.01). All measurements made at presyncope did not show diurnal variation (P > 0.05), but the changes over time (from baseline to presyncope time) in arterial blood pressure, estimated peripheral vascular resistance, and alpha-index baroreflex sensitivity were greater during the morning tests (P < 0.05). These data indicate that tolerance to an incremental orthostatic challenge is markedly reduced in the morning due to diurnal variations in the time-based decline in blood pressure and the initial cerebral blood flow velocity "reserve" rather than the circulatory status at eventual presyncope. Such information may be used to help identify individuals who are particularly prone to orthostatic intolerance in the morning.