As an extension of our studies on vascular responses to endotoxemia, we evaluated sequential ultrastructural lesions of splenic red pulp and correlated these lesions with coagulation changes observed in rhesus monkeys following infusion with endotoxin either as a single bolus (10 mg. per kg.) or at a continuous rate of 10 mg. per kg. per hour for periods up to 16 hours. Controls included monkeys infused with Ringer's lactate solution. Progressive reactions of the splenic cords included increased phagocytic activity of macrophages in association with aggregation and degranulation of platelets and prominent fibrinous deposits characteristically abutting basement membranes of endothelial and reticular cells. The sinuses demonstrated endothelial damage, platelet-fibrin microthrombi obstructing interendothelial slits, and severe engorgement with entrapment of erythrocytes by tactoids of fibrin. The thrombotic lesions of the red pulp developed earlier than similar lesions in hepatic sinusoids, and they were accompanied by progressive thrombocytopenia and disseminated intravascular coagulation. The findings suggest that the unique microcirculation of the spleen is an early target and trigger of endotoxin-induced microthrombosis. It is proposed that phagocytosis of endotoxin by splenic phagocytic cells and associated inflammatory events result in disruption of reticular cells and endothelium leading to massive microthrombosis with breakdown of the splenic filter. In addition, rapid activation of coagulation mechanisms in the red pulp as well as liver sinusoids may promote the development of thrombocytopenia and disseminated intravascular coagulation in endotoxic shock.