Cerebral blood flow (CBF) is typically reduced during stable non-rapid eye movement (non-REM) sleep compared with the waking level. It is not known when in the sleep cycle these changes occur. However, spontaneous fluctuations in alpha and theta rhythm during sleep onset are associated with marked changes in cardio-respiratory control. The aim of this study was to test the hypothesis that changes in CBF would occur during sleep onset and would be related to changes in cortical activity. Middle cerebral artery velocity (MCAV) was measured using transcranial Doppler ultrasound, as an index of CBF, in 10 healthy subjects. Sleep state, ventilation, end tidal carbon dioxide (PET,CO2), arterial oxygen saturation (SaO2), mean arterial blood pressure (MABP) and cardiac R-R interval (RR) were monitored simultaneously. Immediately following the transition from alpha to theta rhythm (the transition from wake to sleep), ventilation decreased by 13.4% and tidal volume (VT) by 12.2% (P<0.01); PET,CO2 increased by 1.9% (P<0.01); respiratory frequency (fR) and SaO2 did not change significantly. MCAV increased by 9.7% (P<0.01); MABP decreased by 3.2% (P<0.01) but RR did not change significantly. Immediately following the transition from theta to alpha rhythm (spontaneous awakening), increased by 13.3% (P<0.01); VT increased by 11.4% (P<0.01); PET,CO2 decreased by 1.9% (P<0.01); MCAV decreased by 11.1% (P<0.01) and MABP decreased by 7.5%; fR, SaO2 and RR did not change significantly. These changes in MCAV during sleep onset cannot be attributed to changes in ventilation or MABP. We speculate that the changes in cerebral vascular tone during sleep onset are mediated neurally, by regulatory mechanisms linked to the changes in cortical state, and that these mechanisms are different from those regulating the longer-term reduction in CBF associated with stable non-REM sleep.