Purpose: In periprosthetic osteolysis, cytokines, which are secreted from macrophages by the stimulation of particles, up-regulate the signaling for osteoclast activation through RANKL (Receptor activator of Nuclear Factor Kappa-B Ligand). This study compared the reaction to the particles and RANKL in the macrophages by examining the changes in the pro-inflammatory signals. In addition, because erythromycin has an anti-inflammatory effect, the effect of erythromycin on the pro-inflammatory signals by particles and RANKL was also analyzed to clarify the mechanism for the anti-resorptive effect with particles. Materials and Methods: The Raw 264.7 cell line (murine macrophage cell line) was used for these experiments. The particles were made from PMMA (poly-methyl-meth-acrylate) and UHMWPE (ultra high molecular weight polyethylene) to enhance their stimulatory effects. Under the same culture conditions used for macrophages, the cells were treated with either particles or RANKL. The differences in the production of TNF-α, activities of MAP kinase, I-κB and reactive oxygen species (ROS) between the particle and RANKL treated macrophages were examined. The influence of erythromycin on these models was also observed. Results: Erythromycin inhibited ERK and p38 phosphorylation in both models, and suppressed the increase in H2O2 production in the particle-treated macrophages. However, erythromycin inhibited neither the production of TNF- in both models nor the production of H2O2 in the RANKL-treated macrophages. In addition, erythromycin reversed the suppression of I-κB by the particles. Conclusion: For the response of macrophages, erythromycin mainly suppresses the particle induced ROS and NF-κB activation compared with RANKL-induced osteoclastogenesis signaling. Erythromycin might suppress particle-induced osteolysis through these anti-inflammatory effects. Therefore, further studies on the downstream signals of osteoclastogenesis will be needed.