Prosthetic mechanical heart valve (MHV) implantation requires lifelong anticoagulation. Overdosage of anticoagulation increases the risk of bleeding, while suboptimal therapy may induce thromboembolism. Inspired by the negative charge of the endothelial glycocalyx, which repels platelets and anionic proteins, we developed an MHV assembly that applies a negative potential to the valve’s blood‑contacting surfaces. Early in vitro work showed that imposing ~ 0.5 V across a bileaflet MHV reproduces the anti-thrombotic behavior of the endothelium. Here we test this MHV assembly in vivo using a swine model. Four Pigs were implanted in the standardization phase with the first design of the MHV assembly; In the experimental phase, three pigs (test group) received the redesigned MHV assembly, and three control pigs received the MHV without electrical activation. Pigs were monitored for 20 weeks after cessation of dual antiplatelet therapy. All four standardization phase test animals succumbed to valve thrombosis. Following the implantation of the redesigned electrically activated MHV assembly, the three test animals survived to the end of the study without valve thrombosis, while two of the three controls died with valve thrombosis. These findings support electrical neo‑endothelialization as a viable strategy to eliminate the need for long-term systemic anticoagulation after MHV implantation.