Osteoimmunomodulation is the interaction of the immune and skeletal systems during biomaterial-mediated osteogenesis. Based on this concept, biomaterials with osteoimmunomodulatory effects have been developed, and they have proven effective in improving the osteogenic capacity of bone biomaterials. Bioactive ions have shown significant effects on modulating osteoimmune response and have demonstrated highly tunable properties. The osteoimmunomodulatory effect differs from ionic concentration and different ion combinations. This suggests that bioactive ion-based strategy is effective for tuning the osteoimmune environment. This chapter summarizes related studies on bioactive ion-mediated osteoimmunomodulatory effects as well as the mechanisms for how these ions modulate local immune response and subsequently influence osteogenesis, which would provide valuable knowl- edge for the development of bone-substitute materials containing “osteoimmune-smart” bioactive ions.