We examined a novel mouse model of wear debris-induced prosthesis instability and osteolysis, and its application for the evaluation of therapy. A stainless steel or titanium-alloy pin was implanted into the proximal tibia to form a contiguous surface with the articular cartilage. In some mice, titanium particles were injected into the tibial canal during the surgery, followed by monthly intraarticular injection. MicroCT scans revealed that the implants without particle challenge were stable without bone mineral density changes for 6 months. Histological analysis showed new bone formation around the implant at 6 weeks postsurgery. Periprosthetic soft tissue with inflammatory cells was a ubiquitous finding at the interface between the implant and surrounding bone in samples exposed to titanium particles, and expression of IL-1β, TNFα, and CD68 was common in these joints. Pullout tests indicated that an average 5N load was required to pull out stable implants from surrounding bone. However, particle stimulation dramatically reduced the pullout force to less than 0.4 N. The feasibility of in vivo gene transfer on this model was confirmed by X-gal staining of synovial membrane and periprosthetic tissue after injection of AAV-LacZ in the prosthetic joint. This murine model of weight-bearing knee prosthesis provides an economical, reproducible, and easily obtained means to study joint arthroplasty failure. The ability to evaluate the biomechanical properties of the prosthetic joint, in addition to histological and biochemical examination, results in a useful model to investigate many of the properties of prosthetic joint components during the response to debris-associated osteolysis.