The introduction of vitamin E-blended ultra-high molecular weight polyethylene (VE-UHMWPE) for use in prosthetic components of hip implants has resulted in the production of implants that have excellent mechanical properties and substantially less adverse cellular responses. Given the importance of a biological response to wear in the survival of a prosthesis, we generated wear debris from UHMWPE that had been prepared with different concentrations of vitamin E of 0.1, 0.3, 0.5, and 1% and evaluated their biological reaction in vitro and in vivo. All types of VE-UHMWPE debris promoted a significantly lower expression of Tnf-α in murine peritoneal macrophages than that induced by conventional UHMWPE debris. However, levels of Tnf-α were not significantly different among the macrophages that were stimulated with VE-UHMWPE wear at the concentrations tested. The ability of wear debris to induce inflammatory osteolysis was assessed in a mouse calvarial osteolysis model. The expressions of Tnf-α, Il-6, and Rankl in granulomatous tissue formed around the wear debris were significantly reduced in mice that had been implanted with 0.3%VE-UHMWPE debris as compared to the corresponding values for mice that had been implanted with UHMWPE debris. Consistent with this finding, 0.3%VE-UHMWPE debris showed the lowest osteolytic activity, as evidenced by the reduced bone resorption area, the degree of infiltration of inflammatory cells and the TRAP staining area. Our results suggested that a 0.3% vitamin E concentration is the most appropriate concentration for use in prosthetic components with a reduced adverse cellular response for prolonging the life-span of the implant.