We performed this study to determine if isolated hypoproteinemia and low colloid osmotic pressure cause formation of fetal edema. We successfully operated on six sets of twin fetal sheep at 114 d gestation to insert catheters into arteries and veins of both fetuses, allowing us to chronically perform partial exchange transfusions. One twin underwent protein reduction by repeated partial exchange transfusion over 3 d, and the other twin underwent simultaneous sham procedures. We removed an average of 18 g of protein, causing a 41% decrease in plasma protein concentration and a 44% decrease in colloid osmotic pressure. Vascular pressures, heart rate, hematocrit, plasma osmolarity, arterial pH, and arterial PO2 were not affected by protein reduction or by sham procedure, whereas PCO2 increased by a small amount in both groups. At autopsy, none of the fetuses in either group were edematous. Measurements of total body water by the wet to dry method, chloride space, and amniotic and allantoic fluid volumes were similar in both groups. We conclude that hypoproteinemia of a short duration does not affect the body water content of fetal sheep.