Tumor necrosis factor-alpha (TNF-alpha) is acutely expressed following focal cerebral ischemia, but its pathophysiological role remains to be extensively characterized. In this study we determined the effect of inhibiting TNF-alpha on the microvascular perfusion impairment and ischemic injury induced by permanent middle cerebral artery occlusion (MCAO). TNF-alpha activity was inhibited with recombinant type I soluble TNF receptor (TNFbp; 1 mg/kg i.v., 0.5 h pre- or post-MCAO). TNFbp significantly attenuated the microvessel perfusion impairment observed in vehicle treated rats, particularly in perifocal/penumbral regions of cortex, and significantly reduced (by 34-38%) the total volume of ischemic injury. These results demonstrate that TNF-alpha contributes to focal ischemic injury and that inhibition of TNF-alpha can confer dramatic neuroprotection. The association of the neuroprotective effect of TNFbp with improved microvascular perfusion suggests that inflammatory and vascular responses to TNF-alpha contribute to its pathological action.