PURPOSE: This work aimed to study and compare the behavior of macrophages and human osteoclast-like cells cultured in contact with four commercial bone substitute materials used as graft for ridge augmentation techniques. Two materials are of natural origin and two are synthetic bone substitutes. METHODS: Macrophage activation and cytokine release were assessed using SEM analysis and a sandwich ELISA kit while the activity of human osteoclast-like cells was studied quantifying calcium released from the substrata studied together with SEM analysis of cell morphology and pit formation on the bone substitutes. RESULTS: Hydroxyapatite proved to be the greatest macrophage activator, while the bovine derived material turned out to be the only bone substitute that does not induce macrophages to release IFN?. No material had direct induction of osteoclast precursor differentiation even if mature osteoclasts showed the highest activity on the human derived material followed by bone ceramic, while the bovine derived material was the substrate with the least osteoclast activity. CONCLUSIONS: The four materials reacted differently with the cells tested and between them, the bovine derived bone, being the lowest macrophage and osteoclast activator may be considered a good bone substitute for clinical situations requiring greater time of permanence of the material at the site of implantation, while human derived bone will be more suitable for clinical applications that require lower time of permanence.