Although it is generally accepted that a decrease in plasma oncotic pressure may result in the formation of peripheral edema, the effect of a hypo-oncotic state on brain water content is less well known. Therefore, utilizing the technique of hollow-fiber plasma-pheresis to manipulate plasma composition, the authors examined the effects of acute changes in either plasma osmolality or colloid oncotic pressure on the EEG, regional cerebral blood flow, intracranial pressrue, and brain tissue specific gravity (as a measure of cerebral water content) in anesthetized, neurologically normal New Zealand white rabbits. Animals in which either osmolality or oncotic pressure was decreased by plasma replacement with an appropriate solution were compared with a group of control animals in which both of these variables were maintained constant. Animals in which plasma osmolality was decreased by 13 ± 6 mOsm/kg (from a baseline value of 295 ± 5 mOsm/kg) showed evidence of a significant increase in cortical water content (~ 0.5%), whereas a 65% reduction in oncotic pressure (from 20 ± 2 mmHg to 7 ± 1 mmHg) failed to produce any change. There were no significant differences in mean arterial pressure, central venous pressure, regional cerebral blood flow, or the EEG between any of the groups. Although intracranial pressure increased in all groups, the largest increase (8.1 ± 4.4 mmHg) occurred in those animals whose osmolality was reduced. The increase in intracranial pressure in animals rendered hypo-oncotic was no different form the 'control' group (2.4 ± 0.9 mmHg vs. 3.0 ± 1.5 mmHg). This study suggests that an acute fall in oncotic pressrue does not promote an increase on cerebral water content in the non-injured brain. Unlike peripheral tissues, the presence of the blood-brian barrier with its small pore size and limited permeability may serve to enhance the importance of osmolality and minimize the role of oncotic pressure in determining water movement between the vasculature and brain tissue.