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Factor VIIIc is a large regulatory cofactor glycoprotein in the blood coagulation containing 6 sequential domains arranged in the order of A1‐A2‐B‐A3‐C1‐C2. The circulating factor VIII protein however is a metal bridged heterodimer consisting of a heavy chain (A1‐A2‐B) and a light chain (A3‐C1‐C2). Its deficiency leads to a congenital bleeding disorder, Hemophilia A. We have shown expression of Factor VIIIc‐like glycoprotein in capillary endothelial cells (i.e., eFactor VIIIc) as a 270 kDa asparagine‐linked (N‐linked) glycoprotein in which the heavy chain Mr 210,000 and the light chain Mr 46,000 dalton are joined together by disulfide‐bridge(s). eFactor VIIIc expression preceding the endothelial cell proliferation and its N‐glycosylation upregulation by cAMP signaling correlating the cellular proliferation further supported its role in angiogenesis. The objective of our study has been to understand the role of eFactor VIIIc in the angiogenic process. The results supported that (i) inhibition of eFactor VIIIc N‐glycosylation with tunicamycin inhibited angiogenesis; (ii) cells cultured in the presence of anti‐Factor VIIIc monoclonal antibody failed to invade the Matrigel(tm) matrix; and (iii) tunicamycin treatment exhibited considerable inhibition of Matrigel(tm) invasion. Thus, we conclude that eFactor VIIIc is involved in matrix dissolution during tumor invasion of blood vessels by activating the matrix metalloproteinases (MMPs). Supported in part by grants G12‐RR03035 (KB) and the Susan G. Komen for Cure BCTR0600582 (DKB).