Cerebrospinal fluid drainage is a first line treatment used to manage severely elevated intracranial pressure (> or = 20 mm Hg) and improve outcomes in patients with acute head injury. There is no consensus regarding the optimal method of cerebrospinal fluid removal. The purpose of this investigation was to determine whether cerebrospinal fluid drainage decreases intracranial pressure and improves cerebral perfusion and to identify factors that impact treatment effectiveness. This study involved 31 severely head injured patients. Intracranial pressure and other indices of cerebral perfusion (cerebral perfusion pressure, cerebral blood flow velocity, and regional cerebral oximetry) were measured before, during, and after cerebrospinal fluid drainage. Arterial and jugular venous oxygen content was measured before and after cerebrospinal fluid drainage. Patients underwent three randomly ordered cerebrospinal fluid drainage protocols that varied in the volume of cerebrospinal fluid removed (1 mL, 2 mL, and 3 mL) for a total of 6 mL of cerebrospinal fluid removed. There was a significant change in the intracranial pressure from a mean at baseline of 26.1 mm Hg (SD = 4.4) to 22.1 mm Hg immediately after drainage. One third of patients experienced a decrease in the intracranial pressure below 20 mm Hg; in two patients the intracranial pressure dropped less than 1 mm Hg. The following factors predicted 61.5% of the variance in the responsiveness of intracranial pressure to drainage: vecuronium hypothermia, baseline cerebral perfusion pressure and acuity of illness. Cerebrospinal fluid drainage provides a transient decrease in intracranial pressure without a measurable improvement in other indices of cerebral perfusion.