Objective To investigate the effects of hypertonic sodium chloride hydroxyethyl starch 40 (HSH40) on cerebral perfusion of pigs with traumatic brain injury (TBI) and hemorrhagic shock. Methods Models of TBI, acute intracranial hypertension and hemorrhagic shock were established in 12 miniature pigs under anesthesia and mechanical ventilation by controlled cortical impact, epidural balloon method and blood withdrawal via femoral artery. One hour after model establishment, animals were divided into three groups (n=4), and were intravenously infused with hydroxyethyl starch 200/0.5 (HES group, equivalent volume of removed blood), hypertonic saline 7.5% (HS group, 20% volume of removed blood) and HSH40 (HSH group, 35% volume of removed blood), respectively. Physiological data, including mean arterial pressure(MAP), intracranial pressure(ICP) and cerebral perfusion pressure (CPP) were observed before model establishment(T01), 60 min after model establishment (before resuscitation)(T0) and 15 min(T15), 30 min(T30), 60 min(T60), 120 min(T120) and 180 min(T180) after resuscitation. Besides, changes of serum sodium, plasma osmotic pressure(OSM), arteriovenous oxygen difference (Da-jvO2) and cerebral oxygen enhancement ratios (OER) of T01, T0, T15, T60 and T120 were observed. Results After resuscitation treatment, MAP in each group significantly increased (P<0.05), and the increase in HSH group was the fastest. After reaching the peak, MAP in HSH group and HES group slowly decreased, while MAP in HS group decreased fast. After resuscitation treatment, ICP in HSH group and HS group of each time point decreased significantly (P<0.05), whereas an elevated ICP occurred in HES group (P<0.05 except for T15). After resuscitation treatment, CPP in each group increased fast, and decreased after reaching the peak, with CCP of each time point significantly higher than those of T0 (P<0.05). CPP in HSH group and HS group increased faster than that in HES group, with HSH group higher than HES group at each time point after resuscitation treatment (P<0.05) and higher than HS group after reaching the peak (P<0.05). Da-jvO2 and OER of T0 in each group were significantly higher than those of T01 (P<0.05), and Da-jvO2 and OER of time points after resuscitation treatment were significantly lower than those of T0 (P<0.05). OER in HS group and HSH group of T60 decreased to those of T01 (P>0.05), while OER of T120 was significantly higher than that of T01 in HS group (P<0.05). Serum sodium and OSM of each time point after resuscitation treatment were significantly higher than those of T0 in HSH group and HS group (P<0.05), and the peak values reached at T15. Conclusion HSH40 (6.6 mL/kg) can effectively resuscitate MAP, reduce ICP, increase CCP and cerebral blood flow, and improve the balance of supply and demand of cerebral oxygen of pigs with TBI and hemorrhagic shock.