Abstract Objectives The occurrence of multinucleated giant cells ( MNGC s) on bone substitute materials has been recognized for a long time. However, there have been no studies linking material characteristics with morphology of the MNGC s. The aim was to analyze the qualitative differences of MNGC s on two commercially available calcium phosphate bone substitute materials retrieved from bone defects. Material and methods Six defects were prepared bilaterally in the mandibular body of three mini pigs. The defects were randomly grafted with either deproteinized bovine bone mineral ( DBBM ) or biphasic calcium phosphate ( BCP ). After a healing period of four weeks, bone blocks were embedded in LR White resin. Three consecutive sections per defect were analyzed as follows: two with light microscopy using toluidine blue and tartrate‐resistant acid phosphatase ( TRAP ) staining and one with transmission electron microscopy. Results Multinucleated giant cells appeared on both biomaterials. On BCP , MNGC s had a flat morphology and were not observed in resorption lacunae. On DBBM , the MNGC s appeared more round and were often found in shallow concavities. MNGC s on both biomaterials demonstrated a varying degree of TRAP staining, with a tendency toward higher staining intensity of MNGC s on BCP . At the ultrastructural level, signs of superficial dissolution of BCP together with phagocytosis of minor fragments were observed. MNGC s on the surface of DBBM demonstrated sealing zones and ruffled borders, both features of mature osteoclasts. Conclusion MNGC s demonstrated distinctly different histological features depending on the bone substitute material used. Further research is warranted to understand the clinical implications of these morphological observations.