To study the effect of oncotic pressure on brain water content during cardiopulmonary bypass (CPB), 14 anesthetized New Zealand White rabbits underwent 60 min of nonpulsatile CPB at normothermia. Animals were grouped according to the composition of the circuit priming fluid. Group 1 animals (n = 7) received a priming fluid (6.5% hydroxyethyl starch in 0.72 N NaCl; 323 ± 13 mOsm/ kg [mean ± SD]) that maintained normal colloid oncotic pressure (COP) during CPB (19.0 ± 1.5 mmHg). Group 2 animals (n = 7) received a priming fluid (0.9 N NaCl; 324 ± 23 mOsm/kg) that led to a hypooncotic state (COP = 6.2 ± 1.2 mmHg). Blood chemistries and hemodynamics were recorded every 15 min during CPB. Animals were given additional priming fluid and sodium bicarbonate during CPB to maintain a circuit flow of 85 ml·kg−1·min−1and arterialpH greater than 7.35. There were no significant differences between groups 1 and 2 with respect to temperature, central venous pressure, mean arterial pressure, PaO2, PaCO2on plasma sodium concentration, or osmolality at any time during CPB, although osmolality increased in both groups. After 60 min of bypass, animals were killed and organ water contents were determined by wet/dry weight ratios. A separate group of nine similarly prepared and anesthetized animals that did not undergo cannulation or CPB also underwent measurement of plasma chemistries and tissue water contents and served as nonbypass controls (group 3). Brain and kidney water contents were unaffected by oncotic pressure, whereas duodenum and skeletal muscle had significantly greater water content (P= 0.003 andP= 0.008, respectively) after hypooncotic CPB. To maintain flow andpH, group 2 (hypooncotic) animals required an average of 313 ± 82 ml additional fluid and 14 ± 7 mEq bicarbonate, whereas group 1 (isooncotic) animals required only 21 ± 27 ml additional fluid (P= 0.0001) and 3 ± 4 mEq bicarbonate (P= 0.0025). All tissue water contents were identical between the control (group 3) and group 1 animals. These results indicate that the mechanisms that maintain brain fluid balance remain intact during nonpulsatile hypooncotic CPB. Fluid and bicarbonate requirements, and edema formation in other tissue beds can be minimized by maintenance of normal oncotic pressure during CPB.