It is widely held that the plasminogen (Plg) system plays a role in inflammation through plasmin-mediated directional cell migration. However, substantial evidence for its involvement in the inflammatory response has been obtained from indirect studies and lacks firm biological confirmation. To directly characterize plasminogen's involvement in the inflammatory response, we used thioglycollate to induce a peritoneal inflammatory reaction in Plg(+/+), Plg(+/-), and Plg(-/-) mice. At 6 hours poststimulation, neutrophil recruitment into the peritoneum was maximal and similar between Plg(+/+), Plg(+/-), and Plg(-/-) mice. In contrast, monocyte recruitment was significantly diminished after 24 hours poststimulation in Plg(-/-) mice relative to Plg(+/+) mice. Lymphocyte recruitment also was blunted. Blood monocyte levels in these mice indicated that diminished recruitment into the peritoneum was not the result of a diminished source of cells in the circulation. Macrophage phagocytic function was similar between Plg(+/+) and Plg(-/-) mice. This study establishes a direct involvement of plasminogen in monocyte recruitment during a representative inflammatory response.