The neuroprotective effect of magnesium chloride (MgCl2), a compound previously demonstrated to improve behavioral and neurochemical outcome in several models of experimental brain injury, was evaluated in the present study. Male Sprague-Dawley rats were anesthetized and subjected to lateral fluid-percussion brain injury of moderate severity (2.5-2.8 atm). A cannula was implanted in the left femoral vein and at 1 h following injury, animals randomly received a 15 min i.v. infusion of either MgCl2 (125 micromol/rat) or saline. A second group of animals received anesthesia, surgery, and either MgCl2 or vehicle to serve as uninjured (sham) controls. Two weeks following brain injury, animals were sacrificed, brains removed, and coronal sections were taken for quantitative analysis of cortical lesion volume and hippocampal CA3 cell counts. Traumatic brain injury resulted in a lesion in the ipsilateral cortex and loss of pyramidal neurons in the CA3 region of the hippocampus in vehicle-treated animals (p < 0.01 vs. uninjured animals). Administration of MgCl2 significantly reduced the injury-induced damage in the cortex (p < 0.01) but did not alter posttraumatic cell loss in the CA3 region of the ipsilateral hippocampus. The present study demonstrates that, in addition to its beneficial effects on behavioral outcome, MgCl2 treatment attenuates cortical histological damage when administered following traumatic brain injury.