Two major issues in total joint arthroplasty are loosening of implants and osteolysis caused by wear particle-induced inflammation. Wear particles stimulate the release of pro-inflammatory cytokines, chemokines and other inflammatory mediators from macrophages and other cells. Although the biological response of macrophages to wear debris is well established, the role of other cell types such as natural killer T lymphocytes (NKT) and dendritic cells (DCs) is limited. Here we show that ultra-high molecular weight polyethylene (UHMWPE) particles stimulate NKT cells to secrete Interferon-γ (IFN-γ); co-culture with DCs further enhanced IFN-γ secretion. Furthermore, UHMWPE particles did not stimulate NKT cells to secrete IL-4, while the NKT cell natural ligand α-Galactosylceramide (α-GalCer) treatment in the co-culture system significantly enhanced both IFN-γ and IL-4 expression by NKT cells. Comparatively, NKT cells and/or DCs exposed to polymethylmethacrylate particles did not stimulate Interferon-γ or IL-4 expression. Mouse bone marrow derived macrophage polarization by lipopolysaccharide and conditioned medium from NKT cells and/or DCs exposed to UHMWPE particles increased TNF-α, but reduced arginase-1 expression in macrophages. The current findings indicate that UHMWPE particles stimulate NKT cells/DCs to produce pro-inflammatory cytokines; this pathway is a novel therapeutic target to mitigate wear particle induced peri-prosthetic osteolysis.