Signaling of RANK (receptor activator of nuclear factor kappa B) through its ligand RANKL appears critical in osteolysis associated with aseptic loosening (AL). The purpose of this study was to investigate the role of RANK in a murine osteolysis model developed in RANK knockout (RANK-/-) mice. Ultra high molecular weight polyethylene (UHMWPE) debris was introduced into established air pouches on RANK-/- mice, followed by implantation of calvaria bone from syngeneic littermates. Wild type C57BL/6 (RANK+/+) mice injected with either UHMWPE or saline alone were included in this study. Pouch tissues were collected 14 days after UHMWPE inoculation for molecular and histology analysis. Results showed that UHMWPE stimulation induced strong pouch tissue inflammation in RANK-/- mice, as manifested by inflammatory cellular infiltration, pouch tissue proliferation, and increased gene expression of IL-1β, TNFα, and RANKL. However, the UHMWPE-induced inflammation in RANK-/- mice was not associated with the osteoclastic bone resorption observed in RANK+/+ mice. In RANK+/+ mice subjected to UHMWPE stimulation, a large number of TRAP+ cells were found on the implanted bone surface, where active osteoclastic bone resorption was observed. No TRAP+ cells were found in UHMWPE-containing pouch tissues of RANK-/- mice. Consistent with the lack of osteoclastic activity shown by TRAP staining, no significant UHMWPE particle-induced bone resorption was found in RANK-/- mice. A well preserved bone collagen content (Van Gieson staining) and normal plateau surface contour [microcomputed tomography (μCT)] of implanted bone was observed in RANK-/- mice subjected to UHMWPE stimulation. In conclusion, this study provides the evidence that UHMWPE particles induce strong inflammatory responses, but not associated with osteoclastic bone resorption in RANK-/- mice. This indicates that RANK signaling is essential for UHMWPE particle-induced osteoclastic bone resorption, but does not participate in UHMWPE particle-induced inflammatory response.