Studies were carried out in unanesthetized dogs to determine the relative importance of neural, endocrine, and colloid osmotic pressure (COP) in the diuretic and natriuretic responses associated with volume expansion. Renal excretory responses to 30-min intravenous infusions of isotonic saline (400 ml) or whole blood (100 ml) were compared while various controllers of sodium and water excretion were either eliminated or held constant. Dogs were studied in the normal state; with plasma arginine vasopressin (AVP) fixed by intravenous infusion; with bilateral renal denervation and plasma AVP fixed; renal denervated with plasma AVP, angiotensin II, aldosterone, atrial natriuretic factor fixed; and renal denervated with these same hormones fixed and with renal arterial pressure servo-controlled at a constant level. Normal uncontrolled dogs increased sodium and water excretion nearly fourfold by the end of the saline load and excreted 85% of the load within 5 h. Urine excretion was minimally affected when the various neural and endocrine controllers were fixed or eliminated. There were no changes of mean arterial pressure with the saline volume loads, but COP fell 2.5 mmHg. Equivalent expansion of the blood volume (100 ml) with whole blood in which COP was unchanged resulted in nearly no increase of urine excretion in renal-denervated dogs with plasma hormones fixed and renal perfusion pressure held constant. We conclude that the rapid diuresis and natriuresis following isotonic volume expansion is predominantly a result of plasma protein dilution and a reduction of COP.