The science of biomaterials is currently expanding towards a very prominent future. Despite the increasing usage of biomaterials in implantable medical devices, little is known about biocompatibility at the molecular level. This study presented here investigates the biocompatibility of specific materials that are currently used for orthopaedic applications;​ Ultra-high molecular weight polyethylene, silicone, and bone allografts as well as a novel biomaterial, chitosan. Once biomaterials are inserted into the body, proteins from the serum and the surrounding environment spontaneously adsorb onto the biomaterial. When the surrounding proteins adhere to the biomaterials they are denatured or damaged. We hypothesize that these proteins will appear foreign to the host immune system, causing an immune response. In certain individuals, this adverse response can ultimately cause failure of the implantable medical devices. By characterizing the interaction between the material surface and the surrounding proteins, we can promote biocompatibility and decrease the host immune responses. Using histological and molecular analysis, we first examined the currently used orthopaedic biomaterials. We identified many individuals that have developed antibodies against the self-proteins that were extracted from the surfaces to the current biomaterials. Some of these proteins were identified and found to be denatured matrix proteins. Secondly, we tested the novel polymer, in both a short and long term in vivo studies. After implantation, the outcome of short-term study was very positive, finding only an inflammatory response with little local or systemic host immune response. However, the long-term results displayed an immune response developing after the eight-month time point and continuing until the final fourteen-month time point. Overall, the results question the biocompatibility of the chitosan scaffolds used in this study. The effects of chitosan need to be addressed before it becomes a clinical used scaffold. These four studies display the need for continual biocompatibility testing of not only the novel materials, but also the current biomaterials. The data supports the hypothesis that immune responses can occur against adherent surface proteins and modifications of the biomaterial to prevent this response would be highly beneficial.