The present study was designed to investigate how octacalcium phosphate (OCP) induces an immune response and whether the response is involved in the biodegradation and subsequent bone formation by OCP implantation in bone defects. Tissue and cellular responses to OCP were compared with those to OCP hydrolyzate (referred to as HL hereafter), which is a Ca-deficient hydroxyapatite (HA) prepared through OCP hydrolysis, by implanting them in rat tibia defects from 5 days to one month. They were also incubated with the macrophage cell line J774.1 for 3 days in vitro. Immunostaining, tartrate-resistant acid phosphatase (TRAP) staining, and histomorphometric analyses indicated that CD68-positive macrophage-like cells, CXCL2-positive cells and TRAP-positive cells accumulated around OCP to a greater extent than HL. In addition, OCP induced more extensive bone formation compared to HL. OCP also enhanced greater IL-6 production and macrophage migration compared to HL. A physicochemical milieu containing calcium ions, which simulates that induced by OCP, also increased macrophage migration. Together, these results suggest that the stimulatory capacity of OCP to induce bone formation can be explained in part by the immune response moderately induced by OCP, which is related to its physicochemical properties.