PURPOSE: Osseointegration-associated infections are a critical barrier to widespread implementation of osseointegrated (OI) prosthetics. To address this challenge, a preclinical animal model must exist of the human model to test potential interventions. In this article, we describe a novel rabbit model of OI implant-related infection that can act as a platform for rapid translation and development of therapeutic approaches to combat these uniquely challenging infections. METHODS: A single-stage amputation was performed by exposure, transection, reaming, and tapping of the tibia, followed by placement of a 75-mm Ti-6Al-4V cortical screw implant. Muscle and skin were closed, and a prosthetic was attached to the screw. Hematology, clinical chemistry, and imaging were performed up to 8 weeks. High-resolution microCT and histology were conducted at terminal end points. Intraosseous vancomycin delivery was compared with intravenous delivery. Serum and bone marrow collection was conducted across a period of 5 hours. RESULTS: Rabbits maintained normal ambulation, mobility, diet, and weight throughout the study period. Clinical chemistry results indicate normal ranges over the study course. microCT and histology demonstrate osseointegration between the threads of the implant within the medullary cavity. Pharmacokinetic data determined that intraosseous vancomycin delivery results in significantly lower vancomycin concentrations systemically compared with intravenous delivery and higher peak vancomycin concentration within the tibial canal. CONCLUSION: This preclinical translational model represents a reproducible small animal model of OI transtibial amputation that successfully recreates the bone-skin-implant interface, material-bone interactions to match human OI, and a similar immune response. Preclinical efficacy of infection interventions will be further explored with establishment of this model.