Osmotherapy is the cornerstone of medical management for cerebral edema associated with large ischemic strokes. We determined the effect of duration of graded increases in serum osmolality with mannitol and hypertonic saline (HS) on blood-brain barrier (BBB) disruption and regional cerebral edema in a well-characterized rat model of large ischemic stroke. Halothane-anesthetized adult male Wistar rats were subjected to transient (2-h) middle cerebral artery occlusion (MCAO) by the intraluminal occlusion technique. Beginning at 6 h after MCAO, rats were treated with either no intravenous fluids or a continuous intravenous infusion (0.3 mL/h) of 0.9% saline, 20% mannitol, 3% HS, or 7.5% HS for 24, 48, 72, and 96 h. In the first series of experiments, BBB permeability was quantified by the Evans blue (EB) extravasation method. In the second series of experiments, water content was assessed by comparing wet-to-dry weight ratios in six predetermined brain regions. Blood-brain barrier disruption was maximal in rats treated with 0.9% saline for 48 h, but did not correlate with increases in serum osmolality or treatment duration with osmotic agents. Treatment with 7.5% HS attenuated water content in the periinfarct regions and all subregions of the contralateral nonischemic hemisphere to a greater extent than mannitol did with no adverse effect on survival rates. These data show that (1) BBB integrity is not affected by the duration and degree of serum osmolality with osmotic agents, and (2) attenuation of increases in brain water content with HS to target levels >350 mOsm/L may have therapeutic implications in the treatment of cerebral edema associated with ischemic stroke.