We hypothesized that endoplasmic reticulum (ER) stress in macrophages induced by wear particles was one of the reasons for particle-induced osteolysis (PIO) in total hip arthroplasty (THA) failure. In the present study, the expression of ER stress markers was examined by Western blot in macrophages treated with particles from materials used in prosthetics, specimens from PIO animal models and patients suffering from aseptic loosening. To address whether ER stress triggers these inflammatory responses, the effect of an ER stress blocker on the expression of inflammatory cytokines in particle-treated macrophages and PIO animal models was tested. The results demonstrated that ER stress markers were significantly upregulated in particle-treated macrophages, periosteum tissues from PIO animal models and clinical specimens of prosthesis loosening. Blocking ER stress with a specific inhibitor dramatically reduced the particle-induced expression of inflammatory cytokines in vitro and in vivo. Furthermore, in PIO animal models, this ER stress blocker dramatically suppressed the differentiation of osteoclasts and reduced the severity of osteolysis. Thus, the results of the present study suggest that ER stress plays a key role in particle-induced osteolysis and that targeting the ER stress pathway may lead to novel therapeutic approaches for the treatment of aseptic prosthesis loosening.