It is well established that cerebral blood flow (CBF) is sensitive to variations in arterial PCO2 (PaCO2) and can be influenced by changes in jugular venous return due to elevated intrathoracic pressure. Therefore, we compared cerebral CO, vasoreactivity when PaCO2 was altered either by changing inspired PCO2 or tidal volume. In addition, we sought to determine if noninvasive transcranial Doppler ultrasonography can be used instead of invasive CBF measurement to determine cerebral CO2 vasoreactivity. In 36 mechanically ventilated patients in coma due to acute brain lesion, we evaluated CBF by continuous jugular thermodilution, middle cerebral artery flow velocity (Vm) by transcranial Doppler ultrasonography, intracranial pressure (ICP; in only 23 of them) by intraventricular catheter, systemic and pulmonary hemodynamic variables, and arterial and jugular bulb blood gases. Measurements were taken at four levels of PaCO2 (25, 30, 35, and 40 mmHg) by modifying in a random order either tidal volume or inspired PCO2. Cerebral, pulmonary, and systemic hemodynamic changes were similar in magnitude during both methods of altering PaCO2. From the highest to the lowest PaCO2, CBF decreased from 61 ± 7 to 36 ± 4 ml/min/100 g (p < 0.001, mean ± SE), Vm from 89 ± 7 to 65 ± 5 cra/s (p < 0.001), and ICP from 29 ± 2 to 12 ± 2 mmHg (p < 0.001), but cerebral perfusion pressure remained constant, ranging from 65 ± 3 to 67 ± 4 mmHg (p = NS). Arteriojugular oxygen content difference increased from 3.2 ± 0.2 to 5.7 ± 0.4 ml/dl (p < 0.001). Eleven of the 20 patients with a preserved CBF response to CO2 survived to 6 months, whereas only two of the 16 patients with an altered response were alive at 6 months (p < 0.05). When compared with CBF by jugular thermodilution, the rates of sensitivity and specificity of transcranial Doppler ultrasonography to detect impaired cerebral CO2 vasoreactivity were 69% and 65%, respectively. In conclusion, the reduction of PaCO2 from 40 to 25 mmHg by modifying either tidal volume or inspired PCO2 resulted in similar effects on cerebral, pulmonary, and systemic circulations. Cerebral CO2 vasoreactivity is of prognostic value in brain-injured patients when determined using CBF but may be misleading when evaluated using velocities measured by transcranial Doppler ultrasonography.