The nature of aseptic prosthetic loosening mainly relates to the wear particles that induce inflammation and subsequent osteoclastogenesis. The ideal approach to impede wear particle-induced osteolysis should minimize inflammation and osteoclastogenesis. In this work, Co29Cr9W3Cu particles were used as a research model for the first time to explore the response of Co29Cr9W3Cu particles to inflammatory response and osteoclast activation in vitro and in vivo by using Co29Cr9W particles as the control group. In vitro studies showed that the Co29Cr9W3Cu particles could promote the generation of M2-phenotype macrophages and increase the expression level of anti-inflammatory factor IL-10, while inhibiting the formation of M1-phenotype macrophages and down-regulating the expression of inflammatory factors TNF-α, IL-6 and IL-1β; More importantly, the Co29Cr9W3Cu particles reduced the expression of NF-κB and downstream osteoclast related-specific transcription marker genes, such as TRAP, NFATc1, and Cath-K; In vivo results indicated that the Co29Cr9W3Cu particles exposed to murine calvarial contributed to decreasing the amount of osteoclast and osteolysis area. These findings collectively demonstrated that Cu-bearing cobalt-chromium alloy may potentially delay the development of aseptic prosthetic loosening induced by wear particles, which is expected to provide evidence of Co29Cr9W3Cu alloy as an alternative material of joint implants with anti-wear associated osteolysis.