We show that u-PA produced by a bone marrow-derived cell is important for the full development of CIA; many inflammatory and destructive mediators are increased in the joints of C57BL/6 mice but not of u-PA-/- mice following CIA development; u-PA-/- mice are essentially resistant to both CAIA and the K/BxN serum transfer model of arthritis; and immune complex-mediated neutrophilia and chemokine production in the peritoneal cavity is u-PA dependent, whereas C5a-mediated neutrophilia is not, suggesting u-PA is acting upstream of C5a signaling. Here, PLAU is linked to arthritic joint disease.