BACKGROUND: Hyperosmolar therapy is the mainstay of treatment to reduce brain bulk and optimize surgical exposure during craniotomy. This study investigated the effect of equiosmolar doses of 7.5% hypertonic saline (HTS) and 20% mannitol on intraoperative cerebral oxygenation and metabolic status, systemic hemodynamics, brain relaxation, markers of cerebral injury, and perioperative craniotomy outcomes. METHODS: A total of 51 patients undergoing elective supratentorial craniotomy were randomly assigned to receive 7.5% HTS (2 mL/kg) or 20% mannitol (4.6 mL/kg) at scalp incision. Intraoperative arterial and jugular bulb blood samples were collected at predefined time intervals for assessment of various indices of cerebral oxygenation; multiple hemodynamic variables were concomitantly recorded. S100B protein and neuron-specific enolase levels were determined at baseline, and at 6 and 12 hours after surgery for assessment of neuronal injury. Brain relaxation and perioperative outcomes were also assessed. RESULTS: Demographic and intraoperative data, brain relaxation score, and perioperative outcomes were comparable between groups. Jugular bulb oxygen saturation and partial pressure of oxygen, arterial-jugular oxygen and carbon dioxide differences, and brain oxygen extraction ratio were favorably affected by 7.5% HTS up to 240 minutes postinfusion ( P <0.05), whereas mannitol was associated with only a short-lived (up to 15 min) improvement of these indices ( P <0.05). The changes in cerebral oxygenation corresponded to transient expansion of intravascular volume and improvements of cardiovascular performance. Increases in S100B and neuron-specific enolase levels at 6 and 12 hours after surgery ( P <0.0001) were comparable between groups. CONCLUSIONS: The conclusion is that 7.5% HTS has a more beneficial effect on cerebral oxygenation than an equiosmolar dose of 20% mannitol during supratentorial craniotomy, yet no clear-cut clinical superiority of either solution could be demonstrated.