In recent experimental studies, we demonstrated a highly beneficial neuroprotective effect of moderate- to high-dose human albumin treatment of transient focal cerebral ischemia, but we did not define the effect of albumin therapy in permanent focal cerebral ischemia. In this study, anesthetized Sprague–Dawley rats were subjected to permanent middle cerebral artery occlusion by retrograde insertion of an intraluminal nylon suture coated with poly-l-lysine. Albumin was administered i.v. at 2 h after onset of middle cerebral artery occlusion, in doses of either 1.25 (n=8) or 2.5 g/kg (n=6). In a separate group of animals, albumin (2.5 g/kg) was given 1 h after middle cerebral artery occlusion (n=6). Vehicle-treated rats (n=6) received 0.9% saline in equivalent volumes. Neurological status was evaluated during and 24 h after middle cerebral artery occlusion. One day after middle cerebral artery occlusion, infarct volumes and brain edema were determined. In a separate group of animals, cortical perfusion was assessed by Laser-Doppler perfusion imaging. Albumin (1.25 g/kg; n=3) or vehicle (sodium chloride 0.9%; n=3) was administered at 2 h after onset of middle cerebral artery occlusion. Higher-dose albumin therapy (2.5 g/kg) significantly improved the neurological score compared to vehicle rats at 24 h, when administered at either 1 or 2 h after middle cerebral artery occlusion. Total infarct volume was reduced by albumin (2.5 g/kg given at 2 h) by 32% compared with vehicle-treated rats. Both albumin doses (1.25 and 2.5 g/kg) significantly reduced cortical and striatal infarct areas at several coronal levels when administered at 2 h after middle cerebral artery occlusion. Brain swelling was not affected by albumin treatment. Cortical perfusion declined during middle cerebral artery occlusion in both groups. Treatment with albumin led to 48% increases in cortical perfusion (P<0.002), but saline caused no change. These results support a beneficial effect of albumin therapy in permanent focal cerebral ischemia.