Total joint replacement (TJR) is very cost-effective surgery for end-stage arthritis. One important goal is to decrease the revision rate, mainly because TJR has been extended to younger patients. Continuous production of ultra-high molecular weight polyethylene (UHMWPE) wear particles induces macrophage infiltration and chronic inflammation, which can lead to periprosthetic osteolysis. Targeting individual pro-inflammatory cytokines directly has not reversed the osteolytic process in clinical trials, owing to compensatory up-regulation of other pro-inflammatory factors. It is hypothesized that targeting the important transcription factor NF-kappaB could mitigate the inflammatory response to wear particles, potentially diminishing osteolysis. In the current study, NF-kappaB activity in mouse RAW 264.7 and human THP1 macrophage cell lines, as well as primary mouse and human macrophages, was suppressed via competitive binding with double strand decoy oligodeoxynucleotide (ODN) containing an NF-kappaB binding element. It was found that macrophage exposure to UHMWPE particles induced multiple pro-inflammatory cytokine and chemokine expression, including TNF-alpha, MCP1, MIP1alpha and others. Importantly, the decoy ODN significantly suppressed the induced cytokine and chemokine expression in both murine and human macrophages, and resulted in suppression of macrophage recruitment. The strategic use of decoy NF-kappaB ODN, delivered locally, could potentially diminish particle-induced periprosthetic osteolysis.