Epithelial cell extrusion during fluid transport was studied under both in vitro and in vivo conditions. The rate of cell extrusion from the villus tips in vitro increased by about onefold in the villi with obstruction of lymph flow associated with the increase of lymph and tissue fluid pressure. When lymph pressure in the jejunal and ileal villi was increased to 6.4 +/- .2 and 12.3 +/- .5 mmHg, respectively, by injection of Ringer solution into the central lacteals, fluid leaked out of the villi and a shedding of epithelium occurred. Vigorous villus spasmodic contraction induced by cocaine or atropine also caused a shedding of epithelium. Cells always appeared in the lumen of intestine in vivo either during fluid absorption or secretion. A copious secretion of fluid, increase of cell loss, and congestion of blood in the villi occurred by the action of cholera toxin, MgSO4, and choline chloride. The rate of cell loss was highest during fluid secretion induced by an elevation of tissue fluid pressure such as at high venous pressure or during intra-arterial histamine infusion. It is thus concluded that elevated tissue fluid pressure is involved in epithelial cell extrusion during fluid transport.