Guinea pig peritoneal macrophages were demonstrated to bind selectively soluble 125I-fibrin and fibrin/fibrinogen complexes as compared with fibrinogen, fibrinogen degradation products, and fibrin degradation products. Cellular uptake was considered to be surface receptor binding on the basis of removal of bound 125I-fibrin by trypsin and because uptake occurred in the presence of metabolic inhibitors. 125I-fibrin uptake could be blocked by nonradioactive fibrin but not by IgG or immune complexes. Binding was uneffected by prior treatment with plasmin or trypsin but was calcium dependent. Only limited reversibility of binding could be demonstrated after prolonged incubation. Scatchard plots permitted an estimate of the number of bound molecules. At saturation 6.92 X 10(6) 125I-fibrin molecules were bound per cell. Similar binding of fibrin was noted in polymorphonuclear leukocytes, but not lymphocytes or fibroblasts. Soluble fibrin binding may be a host defense mechanism whereby the reticuloendothelial system can remove fibrin from the blood before the development of microthrombi.