Antithrombin III (ATIII) is an anticoagulant protein which binds and inactivates thrombin and other serine proteinases. Little is known about regulation of its synthesis. We confirm that ATIII is synthesized by isolated rat hepatocytes, and that its synthesis is not altered by direct feedback of its complexes with proteinases. Neither is hepatocyte synthesis of ATIII altered by supernatants from macrophages cultured in the presence of ATIII-proteinase complexes. However, culture of macrophages with fibrinogen fragment D results in production of a factor(s) in the macrophage supernatants which stimulates hepatic fibrinogen synthesis, as previously described, and also stimulates the synthesis of ATIII and alpha 1-proteinase inhibitor (alpha 1PI). Synthesis of albumin and rat alpha 2-macroglobulin (alpha 2M) is not (alpha 2M) is not altered. Culture of macrophages in the presence of bacterial endotoxin also results in release of a factor(s) into the medium which stimulates the same changes in hepatocyte protein synthesis. These results show for the first time a mechanism by which synthesis of ATIII can be regulated during coagulation and fibrinolysis.