Experiments were conducted to determine the influence of the pancreatic hormones insulin, glucagon, and somatostatin on RES phagocytosis both in vivo and in the isolated perfused livers of rats. Chronic pancreatic hormonal treament consisted of twice daily injection s.c. of NPH insulin with doses ranging from 0.75 U on day 1 to 9.0 U on day 13 and unchanged doses of glucagon (200 .mu.g) and somatostatin (50 .mu.g). Chronic treatment with insulin significantly depressed by 48% intravascular phagocytosis of colloidal carbon administered i.v. at a dose of 8 mg/100 g, while glucagon and somatostatin stimulated macrophage endocytic function by 32% and 26%, respectively, compared to the control value. Acute treatment with the 3 pancreatic hormones at 30 min prior to carbon administration similarly produced insulin depression and glucagon and somatostatin stimulation of RES phagocytosis. Addition of the 3 hormones at near physiologic concentrations (20 ng/ml for insulin, 10 ng/ml for glucagon, and 5 ng/ml for somatostatin) to the recirculating perfusate of isolated perfused rat livers simultaneous with 24 mg of colloidal carbon likewise resulted in phagocytic reduction after insulin and enhancement after glucagon and somatostatin. Experiments involving insulin in vitro with isolated perfused livers and glucose replacement therapy concomitant with insulin in vivo demonstrated that hypoglycemia is not necessary for phagocytic depression by insulin while severe hypoglycemia in the perfusion medium is sufficient to depress carbon uptake by isolated perfused livers independent of insulin. Both pancreatic hormones and the level of glycemia seem to be important in modulating hepatic RES phagocytosis.