Expanded polytetrafluoroethylene (ePTFE) has been successfully used as an artificial vascular graft material owing to its unique merits of fibrous structure, chemical stability, physical robustness, and nontoxicity. However, its insufficient endothelial cell affinity arising from its highly hydrophobic surface nature induces early thrombus formation and development of neointimal hyperplasia, leading to poor long-term patency rates. In this study, we demonstrate a novel rapid surface modification technique, termed as sputtering-based plasma immersion ion implantation (S-PIII), to elicit favorable vascular responses on the ePTFE surface. This technique enables rapid ion implantation of biologically compatible tantalum (Ta) into ePTFE surfaces, generating a nano-thick Ta-rich surface layer (<30 at.%) without any structural defects or loss of ePTFE’s fibrous morphology. Surface properties of ePTFE, such as its biologically inert chemical structure and strong hydrophobicity, are ameliorated considerably after the S-PIII treatment, which is more favorable for endothelial cell (EC) adherence, spreading, and proliferation. In particular, compared to a bare ePTFE surface, Ta-implanted ePTFE possesses an antithrombogenic property, suppressing platelet adhesion and activation on its surface. From an in vivo pilot study with a canine aortic bypass model, Ta-implanted ePTFE demonstrates substantially suppressed early thrombosis with rapid formation of EC monolayers covering the luminal surface.