Following brain injury there is an excessive release of glutamate, a reduction in levels of cellular Mg+ +, and the generation of oxygen free radicals. These processes may contribute to the severity of the behavioral impairments seen following brain injury by leading to secondary neuronal degeneration. The present experiment investigates the relative effects of three drugs (MK-801, an NMDA antagonist; magnesium chloride, an NMDA antagonist; and N-tert-butyl-α-phenylnitrone (PBN), an anti-oxidant and free radical scavenger) which disrupt different aspects of the pathophysiological process, in reducing these impairments. Direct comparisons of these drugs may determine if one treatment is more effective than another, or if one is detrimental. In addition, the effects of combination treatments including PBN and MK-801 or MgCl2 were examined. These combination treatment were aimed at the possibility of potentiating the beneficial effects observed after administration of these agents alone. Rats received unilateral electrolytic lesions of the somatic sensorimotor cortex followed by a regimen of MK-801 (1 mg/kg), MgCl2 (1 mmol/kg), PBN (100 mg/kg), MK-801 + PBN (1 mg/kg, 100 mg/kg), MgCl2 + PBN (1 mmol/kg, 100 mg/kg), or saline (1 ml/kg) beginning 15 min following injury. Rats were tested on several sensorimotor tasks (i.e. forelimb placing and foot-fault) for 43 days following the cortical lesions. Rats receiving any of the single or combination drug treatments showed a significant facilitation of recovery on the sensorimotor tasks compared to saline control rats. On one behavioral test (i.e. foot-fault) there was a significant further enhancement of the recovery by combination treatments compared to the single treatment groups. These data are consistent with the idea that excessive release of glutamate, reduction in Mg+ + levels, and free radical generation contribute to the severity of the behavioral impairments following cortical injury, and that arresting these processes results in a facilitation of behavioral recovery. Anatomical analysis showed that all drug treatments decreased the amount of atrophy seen in the ipsilateral striatum.