The management of cerebral perfusion pressure (CPP) remains a controversial issue in the critical care of severely head-injured patients. Recently, it has been proposed that the state of cerebrovascular autoregulation should determine individual CPP targets. To find optimal perfusion pressure, we pharmacologically manipulated CPP in a range of 51 mm Hg (median; 25th-75th percentile, 48-53 mm Hg) to 108 mm Hg (102-112 mm Hg) on Days 0, 1, and 2 after severe head injury in 13 patients and studied the effects on intracranial pressure (ICP), autoregulation capacity, and brain tissue partial pressure of oxygen. Autoregulation was expressed as a static rate of regulation for 5-mm Hg CPP intervals based on middle cerebral artery flow velocity. When ICP was normal (26 occasions), there were no major changes in the measured variables when CPP was altered from a baseline level of 78 mm Hg (74-83 mm Hg), indicating that the brain was within autoregulation limits. Conversely, when intracranial hypertension was present (11 occasions), CPP reduction to less than 77 mm Hg (73-82 mm Hg) further increased ICP, decreased the static rate of regulation, and decreased brain tissue partial pressure of oxygen, whereas a CPP increase improved these variables, indicating that the brain was operating at the lower limit of autoregulation. We conclude that daily trial manipulation of arterial blood pressure over a wide range can provide information that may be used to optimize CPP management.