We have recently shown that high-dose human serum albumin (HSA) therapy confers marked histological protection in experimental middle cerebral artery occlusion. Thus, the purpose of this study was to determine whether treatment with high-dose HSA would protect in a rat model of traumatic brain injury (TBI). Twenty-four hours prior to TBI, the fluid percussion interface was positioned parasagittally over the right cerebral cortex. On the following day, fasted rats were anesthetized with 3% halothane, 70% nitrous oxide, and 30% oxygen and received right parieto-occipital parasagittal fluid-percussion injury (1.5-2.0 atm). Cranial and rectal temperatures were monitored throughout the experiment and held at normothermic levels (36.5-37.5 degrees C) by a warming lamp above the animal's head. The agent (25% human serum albumin, HSA) or vehicle (sodium chloride 0.9%) was administered i.v. (1% of body weight) 15 min after trauma. Behavioral function was evaluated in all rats before and after TBI (at 2 h, 24 h, 48 h, 72 h, and 7 days). Neurological function was graded on a scale of 0-12 (normal score = 0; maximal score = 12). Seven days after TBI, brains were perfusion-fixed, coronal sections at various levels were digitized, and contusion areas in the superficial, middle and deep layers of cortex and in the underlying fimbria were measured. HSA significantly improved the neurological score compared to saline at 24 h, 72 h, and 7 days after TBI (6.0 +/- 0.6 [albumin] versus 8.4 +/- 0.5 [saline]; 3.6 +/- 0.7 versus 6.8 +/- 1.0; and 2.6 +/- 0.6 versus 5.7 +/- 0.8, respectively; p < 0.05). HSA therapy also significantly reduced total contusion area (0.89 +/- 0.2 versus 1.82 +/- 0.3 mm2; p = 0.02). Our findings document that high-concentration albumin therapy instituted 15 min after trauma significantly improves the neurological score and reduces histological damage. We believe that this pharmacological agent may have promising potential for the clinical treatment of brain injury.