F ibrin deposition within joints is a prominent feature of arthritis, but the precise contribution of fibrin(ogen) to inflammatory events that cause debilitating joint damage remains unknown. To determine the importance of fibrin(ogen) in arthritis, gene-targeted mice either deficient in fibrinogen (Fib^–) or expressing mutant forms of fibrinogen, lacking the leukocyte receptor integrin α_Mβ₂ binding motif (Fibγ^390–396A) or the α_IIbβ₃ platelet integrin-binding motif (Fibγ^Δ5), were challenged with collagen-induced arthritis (CIA). Fib^– mice exhibited fewer affected joints and reduced disease severity relative to controls. Similarly, diminished arthritis was observed in Fibγ^390–396A mice, which retain full clotting function. In contrast, arthritis in Fibγ^Δ5 mice was indistinguishable from that of controls. Fibrin(ogen) was not essential for leukocyte trafficking to joints, but appeared to be involved in leukocyte activation events. Fib^– and Fibγ^390–396A mice with CIA displayed reduced local expression of TNF-α, IL-1β, and IL-6, which suggests that α_Mβ₂-mediated leukocyte engagement of fibrin is mechanistically upstream of the production of proinflammatory mediators. Supporting this hypothesis, arthritic disease driven by exuberant TNF-α expression was not impeded by fibrinogen deficiency. Thus, fibrin(ogen) is an important, but context-dependent, determinant of arthritis, and one mechanism linking fibrin(ogen) to joint disease is coupled to α_Mβ₂-mediated inflammatory processes.