The aim of this study was the investigation of a copper-filled TiO2 coating, that in vitro showed good antibacterial properties combined with good tissue tolerance in an animal model. To better understand the antibacterial mechanism of the bioactive coating the release of copper (Cu) ions over time was monitored to be able to detect possible threats as well as possible fields of application. 30 New Zealand White rabbits were divided into two groups with 15 animals per group. In group 1 (control group) Ti6Al4 V bolts were implanted into the distal femur, in group 2 the Ti6Al4 V bolts were coated with four TiO2-coatings with integrated Cu(2+)-ions (4 × Cu-TiO2). Blood tests were performed weekly until the animals were sacrificed 4 weeks postoperative. The maximum peak of Cu and ceruloplasmin concentration could be seen in both groups one week postoperative, whereas the Cu values in group II were significantly higher. The Cu concentration in both groups approximated the initial basic values 4 weeks postoperative. The 4 × Cu-TiO2 coating tested in our rabbit model for total knee arthroplasty is an active coating that releases potentially antibacterial Cu(2+) for 4 weeks with a peak 1 week postoperative. The bioactive coating could be a promising approach for a use in the field of implant related infection, orthopaedic revision and tumor surgery in the future.