The expression of collagen XVII (BP180), a transmembrane hemidesmosomal component, is upregulated in invasive areas of epithelial tumors. The collagenous ectodomain of collagen XVII is cleaved from the plasma membrane of keratinocytes and malignant epithelial cells. The released ectodomain is predicted to regulate cell detachment, differentiation, and motility. We report that the cell adhesion domain of collagen XVII, Col15, is able to chemotactically attract invasive HSC-3 SCC cells but not keratinocytes. Analysis of integrin expression revealed that HSC-3 cells, unlike keratinocytes, express αIIb integrin, a platelet-specific fibrinogen receptor. We show that this novel chemotactic function is mediated by the known Col15-binding integrins α5β1 and αv and the platelet integrin αIIb. Moreover, we report that tirofiban, a FDA-proved αIIb integrin-blocking drug widely used for the therapy of acute coronary ischaemic syndrome and the prevention of thrombotic complications, inhibits the Col15 chemotaxis of HSC-3 carcinoma cells. Together, these data demonstrate a novel interaction between collagen XVII and αIIb integrin and also suggest a possibility to use tirofiban to inhibit the invasion and progression of αIIb expressing SCC tumors.