Experimental traumatic brain injury (TBI) results in a rapid and significant necrosis of cortical tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the original damage, resulting in significant neurological dysfunction. Young adult animals were treated either 5 min before or immediately after a cortical injury with the immunosuppressant cyclosporin A (CsA). All animals treated with CsA demonstrated a significant reduction in the amount of cortical damage 7 days following TBI. The effect was observed in adult rats and in two different strains of adult mice following systemic administration of the drug. Cyclosporin A has known effects on mitochondria by inhibiting the opening of the permeability transition pore and maintaining calcium homeostasis. These results with a clinically approved drug demonstrate an almost 50% reduction in lesion volume and suggest that the mechanisms responsible for tissue necrosis following TBI are amenable to manipulation. Since CsA also has known interactions with calcineurin and may be providing neuroprotection through that mechanism, additional animals were treated with the immunosuppressant FK 506. FK 506 failed to protect against the cortical damage. Amelioration of cortical damage with CsA indicates that pharmacological therapies can be devised that will significantly alter neurological outcome after injury.