Neurohumoral responses have been implicated in the pathogenesis of ischemia-evoked cerebral edema. In a well-characterized animal model of ischemic stroke, the present study was undertaken to 1) study the profile of plasma arginine-vasopressin (AVP), and 2) to determine if osmotherapy with mannitol and various concentrations of hypertonic saline (HS) solutions influence plasma AVP levels. Halothane-anesthetized adult male Wistar rats were subjected to 2 hr of middle cerebral artery occlusion (MCAO) with the intraluminal filament technique. Plasma AVP levels (pg/ml; mean±SD) were significantly elevated at 24 hr (42±21), 48 hr (50±28), and 72 hr (110±47), and returned to baseline at 96 hr (22±15) following MCAO as compared to sham-operated controls (14±7). Plasma AVP levels at 72 hr were significantly attenuated with 7.5% HS (37±8 pg/mL; 360±11 mOsm/L) as compared to 0.9% saline (NS; 73±6; 292±6 mOsm/L), 3% HS (66±8 pg/mL; 303±12 mosm/L), or mannitol (74±9 pg/mL; 313±14 mOsm/L) treatment. 7.5% HS significantly attenuated water content in the ipsilateral and contralateral hemispheres as compared to surgical shams, NS, 3% HS and mannitol treatments. Peak plasma AVP levels were not associated with direct histopathologic injury to the anterior hypothalamus. Attenuation of brain water content with 7.5% HS treatment coincides with attenuated serum AVP levels, and we speculate that this may represent one additional mechanism by which osmotherapy attenuates edema associated with ischemic stroke.