This study examined the relationship between cerebral blood flow (CBF) and end-tidal PCO2 (PETCO2) in humans. We used transcranial Doppler ultrasound to determine middle cerebral artery peak blood velocity responses to 14 levels of PETCO2 in a range of 22 to 50 Torr with a constant end-tidal PO2 (100 Torr) in eight subjects. PETCO2 and end-tidal PO2 were controlled by using the technique of dynamic end-tidal forcing combined with controlled hyperventilation. Two protocols were conducted in which PETCO2 was changed by 2 Torr every 2 min from hypocapnia to hypercapnia (protocol I) and vice-versa (protocol D). Over the range of PETCO2 studied, the sensitivity of peak blood velocity to changes in PETCO2 (CBF-PETCO2 sensitivity) was nonlinear with a greater sensitivity in hypercapnia (4.7 and 4.0%/Torr, protocols I and D, respectively) compared with hypocapnia (2.5 and 2.2%/Torr). Furthermore, there was evidence of hysteresis in the CBF-PETCO2 sensitivity; for a given PETCO2, there was greater sensitivity during protocol I compared with protocol D. In conclusion, CBF-PETCO2 sensitivity varies depending on the level of PETCO2 and the protocol that is used. The mechanisms underlying these responses require further investigation.