Tissue factor (TF), a transmembrane receptor for plasma factor VII(a), is the main initiator of the coagulation cascade. It has also been implicated in noncoagulant processes, including inflammation. The function of the TF cytoplasmic domain was studied in mice in which 18 of the 20 cytoplasmic amino acids were deleted. This mutation (TF^δCT/δCT) is not associated with alterations in blood coagulation. Arthritis was induced by intra-articular injection of methylated bovine serum albumin (mBSA) in mice preimmunized with mBSA. Arthritis severity was significantly reduced in TF^δCT/δCT mice compared to wild-type mice, including reductions in synovitis, synovial exudate, cartilage degradation, and bone damage. A marked reduction in synovial interleukin (IL)-1β and IL-6 mRNA was also observed. Serum anti-mBSA IgG1, but not IgG2a, was increased in mutant mice. Cutaneous delayed-type hypersensitivity and antigen-induced T-cell proliferation were reduced in TF^δCT/δCT compared to wild-type mice. A significant down-regulation of lipopolysaccharide-induced IL-1, tumor necrosis factor, IL-6, macrophage migration inhibitory factor, and matrix metalloproteinase-13 mRNA was observed in immunized, but not in naive TF^δCT/δCT macrophages ex vivo. These data suggest a significant role for the cytoplasmic domain of TF in the regulation of the immunoinflammatory responses, a murine arthritis model, and macrophage function.