A link between colitis and colon cancer is well established, but the mechanisms regulating inflammation in this context are not fully defined. Given substantial evidence that hemostatic system components are powerful modulators of both inflammation and tumor progression, we used gene-targeted mice to directly test the hypothesis that the coagulation factor fibrinogen contributes to colitis-associated colon cancer in mice. This fundamental provisional matrix protein was found to be an important determinant of colon cancer. Fibrinogen deficiency resulted in a dramatic diminution in the number of colonic adenomas formed following azoxymethane/dextran sodium sulfate challenge. More detailed analyses in mice expressing a mutant form of fibrinogen that retains clotting function, but lacks the leukocyte integrin receptor α_Mβ₂ binding motif (Fibγ^390-396A), revealed that α_Mβ₂-mediated engagement of fibrin(ogen) is mechanistically coupled to local inflammatory processes (e.g., interleukin-6 elaboration) and epithelial alterations that contribute to adenoma formation. Consistent with these findings, the majority of Fibγ^390-396A mice developed no discernable adenomas, whereas penetrance was 100% in controls. Furthermore, the adenomas harvested from Fibγ^390-396A mice were significantly smaller than those from control mice and less proliferative based on quantitative analyses of mitotic indices, suggesting an additional role for fibrin(ogen) in the growth of established adenomas. These studies show, for the first time, a unique link between fibrin(ogen) and the development of inflammation-driven malignancy. Given the importance of antecedent inflammation in the progression of numerous cancers, these studies suggest that therapies targeting fibrin(ogen)-α_Mβ₂ interactions may be useful in preventing and/or treating this important subset of malignancies. Cancer Res; 70(7); 2634–43