Aseptic loosening of joint prosthetics is one of the most frequent reasons for the failure of total joint replacement surgeries. A major cause of the aseptic loosening is osteolysis caused by a periprosthetic inflammatory response to wear particles released from implanted prosthetics. Tumor necrosis factor (TNF)-α is thought to play a dominant role in wear-induced inflammation. It was shown previously by our group, as well as by other researchers, that macrophages produce abundant TNF-α when exposed to particulate titanium (Ti), which is widely used as a biomaterial in arthroplastic surgery. In the present study, we have tested the feasibility of using siRNA as a therapeutic intervention against wear-induced TNF-α production. Our data show that transfection of U937 macrophage cells with TNF-α siRNA inhibits Ti particle-induced expression of TNF-α mRNA and protein by >65%. Moreover, U937 cells transfected with TNF-α siRNA were significantly more resistant to Ti particle-induced apoptosis (>60%, p<0.05) and caspase-3 activation (>50%, p<0.05) compared with normal U937 cells. Collectively, our data show that siRNA can be an effective way to inhibit Ti particle-induced TNF-α expression and the activation of downstream pathways such as apoptosis in macrophages. These data provide a foundation for future studies to investigate the use of siRNA targeting inflammatory cytokines as a therapeutic modality for the treatment of aseptic loosening of prosthetic materials used in arthroplastic surgery.