The role of endogenous extracellular superoxide dismutase (EC-SOD) was examined in a murine model of transient focal cerebral ischemia. Homozygous EC-SOD deficient (EC-SOD-/-; n = 18) and wild type (EC-SOD+/+; n = 19) littermates were anesthetized with halothane and subjected to 50 min of intraluminal middle cerebral artery occlusion with pericranial temperature maintained at 37.0 degrees C. After 24 h of reperfusion, resultant hemiparesis and cerebral infarct size were measured. Total infarct volume was 81% greater (P = 0.03) and hemiparesis was more severe (P = 0.01) in EC-SOD-/- versus EC-SOD+/+ mice. The worsened ischemic outcome observed in EC-SOD-/- mice is consistent with prior work which found transgenic EC-SOD overexpressing mice to exhibit enhanced tolerance to focal ischemia. The results suggest that endogenous antioxidant activity in the extracellular compartment plays an important role in the histologic/neurologic response to focal cerebral ischemia.