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Introduction: Hyperosmotic agents are the mainstay of therapy for intra-cranial hypertension. However, little is known about the cerebral metabolic response to different hyper-osmotic agents. Methods: Pigs (35–45 Kg), anesthetized using a continuous intravenous infusion of midazolam, fentanyl and rocuronium, were managed to achieve normal cardiac output and mean arterial pressure and ventilated to maintain normoxia, normocapnia and normal cerebral perfusion. A balloon catheter was used to increase intracranial pressure (ICP). When ICP reached 30 mmHg, animals were randomized to receive one iso-osmolar load of 255 mOsm/dose of either 20% mannitol (M20%) or 7.45% hypertonic saline (HS 7.45%) as a 30 min bolus through a central vein. The effectiveness of the solution to decrease ICP was arbitrarily defined as an ICP decrease of ≥3 mmHg after the infusion. Measurements of cerebral perfusion (intra-parenchymal pressure, cerebral perfusion pressure, brain oxygen tension, PtO2), systemic perfusion (mean arterial pressure [MAP], cardiac output (CO), serum lactate) and neuronal response (lactate/pyruvate ratio, L/P) were taken at baseline (twice), at ICPs of 15 and 30 mmHg and at T30, T60, T120 and T180 min after the end of the infusion. After 5 hours, the animal was sacrificed. A linear mixed model was used to analyze the time courses of considered variables. Results: All values are express as mean (SD). HS 7.45% administration resulted in lower ICP at T180 min: 27.1 mmHg (11.64) vs. 36.1 mmHg (11.9); mean difference: 9 mmHg ±4.2;p=0.04) and higher PtO2 at T180: 41.0 (14.9) vs. 21.7 (13.1); mean difference: 19.2 mmHg ±7.1 mmHg, p=0.01. We found no significant difference in the L/P ratio at T180 min: 67.5 (31.8) vs. 65.4 (115.41); mean difference: 2.1 ± 34.2, p=0.95, or on MAP, CO or lactate levels between the two groups. Conclusions: In this model, administration of HS 7.45% was more effective than M20% in reducing ICP and increasing PtbO2. These differences were not associated with significant differences in systemic variables or regional metabolism.