Phagocytosis of particulate fibrin has been previously established as a function of the reticuloendothelial system (RES). More recently, reticuloendothelial cells have been shown to bind soluble fibrin/fibrinogen (f/F) complexes in vitro. To quantitate RES clearance vs microthrombus formation, varying doses (0.1-6 mg/kg) of 125I-soluble f/F was injected into rabbits. One hour later the animals were killed, at which time 48 +/- 8% of the 125I f/F had been cleared from the blood. Homogenized organ samples were separated into insoluble pellet, soluble protein bound, and free 125I. Treatment of other samples with plasmin prior to homogenization differentiated the insoluble 125I into RES cleared (intracellular-plasmin resistant) vs microthrombi (plasmin sensitive pellet 125I). 125I-f/F was chiefly found in liver and spleen. Injection of low f/F concentrations resulted in no plasmin sensitive pellet 125I. 3 mg/kg f/F caused small, variable amounts of plasmin sensitive pellet 125I, chiefly in the kidney. With 6 mg/kg, 21-50% of the insoluble 125I in all organs was plasmin sensitive, and occasional 1-2 mm thrombi were found. The data indicate complete and rapid RES clearance of small amounts of soluble f/F from the blood, without microthrombi being formed. The RES was acutely saturated at 1.5-3.0 mg f/F/kg, which is equivalent to immediate conversion to fibrin of 1-2% of the intravascular fibrinogen pool.