Despite improved strategies for treating periprosthetic infection, current antibiotic delivery approaches are imperfect and can result in bacterial resistance and recalcitrant bio-films. To address the issues, we developed a covalently linked vancomycin-titanium implant interface that prevents and possibly eliminates bacterial colonization. We determined the amount of vancomycin immobilized on the titanium surface and assessed vancomycin stability and activity over time. When incubated with Staphylococcus aureus, the vancomycin-titanium surface showed an almost complete absence of adherent bacteria. To determine if continual exposure to vancomycin-titanium would cause decreased susceptibility to the antibiotic, S. aureus was incubated with vancomycin-titanium for 1 week or 4 weeks; these bacteria did not show an increased minimum inhibitory concentration for vancomycin. We tested the long-term stability of the vancomycin-titanium surface by incubation in phosphate-buffered saline for 11 months and then challenging the surface with S. aureus. Fluorescent staining for bacteria indicated the vancomycin-titanium retained its bactericidal activity. Finally, osteoblasts seeded on the vancomycin-titanium surface exhibited no change in viability, indicating the surface supports bone cell adhesion. Based on these observations, covalent modification of the titanium surface with an antibiotic may be viewed as a potential new tool in preventing or eliminating periprosthetic infection.