Fibroblasts from patients with pulmonary fibrosis express higher levels of the receptor for urokinase, and the extent of fibrosis in some animal models exhibit a dependence on urokinase receptor. Recent observations have identified the urokinase receptor as a trans-interacting receptor with consequences on signaling and cell responses that vary depending on its interacting partner, the relative levels of expression, and the state of cellular transformation. We undertook this study to define the u-PAR-integrin interactions, and determine the functional consequences of such interactions on normal human lung fibroblast attachment and migration. u-PAR co-localizes in lammelipodia/filopodia with relevant integrins that mediate fibroblast attachment and spreading on the provisional matrix proteins vitronectin, fibronectin and collagens. Inhibitory antibody studies reveal that human lung fibroblasts utilize v5 to attach to vitronectin, predominantly 51 (and v3) to attach to fibronectin, and 11, 21 and 31 to attach to collagen. Blocking studies with -integrin subunit decoy peptides and u-PAR neutralizing antibodies, indicate that u-PAR modulates the integrin-mediated attachment to purified provisional matrix proteins, to anti-integrin antibodies, or to fibroproliferative lesions from fibrotic lungs. Furthermore, these peptides blunt fibroblast spreading and migration. We show that u-PAR can interact with multiple integrins, but with a preference for 3. Taken together, these data demonstrate that u-PAR may interact with multiple integrins in normal human lung fibroblasts thereby promoting attachment, spreading, and migration. Modulation of u-PAR-integrin interactions can reduce fibroblast migration, and thereby potentially ameliorate fibroproliferative diseases of the lung.