Tumor necrosis factor-α (TNF) is a potent osteoclastogenic cytokine that has a fundamental role in the pathogenesis of implant particle-induced osteolysis. The nuclear transcription factor NF-κB mediates TNF signaling and this transcription complex is necessary for osteoclastogenesis. Because polymethylmethacrylate (PMMA) particles cause osteolysis, we reasoned the PMMA would induce NF-κB activation. In fact, we find that exposure of osteoclast precursors, in the form of colony stimulating factor-1 (CSF-1) dependent murine bone marrow macrophages, to PMMA particles prompts nuclear translocation and activation of NF-κB. Supershift assays confirm the presence of the p50 and p65 NF-κB subunits in the activated transcription factor. Particle-induced NF-κB activation is equal in both wild type and LPS-hyporesponsive cells indicating that the phenomenon does not represent endotoxin contamination. A soluble, competitive inhibitor of TNF (huTNFr:Fc) dampens particle-directed NF-κB activation and this response is also abrogated in TNF-/- osteoclast precursors. Thus, PMMA particle activation of NF-κB is a secondary event resulting from enhanced TNF expression and is independent of LPS contamination.