Fibrin derived from fibrinogen after thrombin cleavage plays an essential role in forming blood clots. Fibrin as well as fibrinogen is also involved in the induction of platelet aggregation, leukocyte cell adhesion and phagocytosis. An additional biological role of fibrin and fibrinogen is presented in this study. One of the proteolytic peptides of fibrin/fibrinogen, fragment E, and not fragment D, was able to stimulate rat peritoneal macrophages to express interleukin-6 (IL-6). The stimulation of fibrin/fibrinogen fragment E on macrophages appeared to work in a dose- and time-dependent manner. Adherent fibrin fragment E was able to stimulate IL-6 expression as well as IL-6 protein production. The effect of fibrin fragment E was inhibited by the addition of an excess amount of GPRP tetrapeptide, but not by GHRP, which are the amino acids derived from the amino terminus of fibrin alpha and beta chains, respectively. These results suggest that fibrin as well as fibrinogen function as a stimulator to macrophages, and leukocyte integrin p150,95 (CD11c/ CD18), not Mac-I (CD11b/CD18), is involved in mediating fibrin stimulatory activity in macrophages.