Multinucleated giant cells appear in a variety forms in different types of oral lesion. However, their nature is still not well understood. Thus, to address this issue, the immunohistochemical characteristics of inflammatory giant cells (Langhans’ giant cells in lesions of tuberculosis and foreign body giant cells in odontogenic keratocysts and squamous cell carcinomas) and tumor giant cells in central giant cell granulomas were compared with those of osteoclasts, the normal giant cell, using a panel of macrophage and osteoclast marker antibodies, such as calcitonin receptor (CT-R), c-Src, Cathepsin K (Cath-K), CD14, RANK, and c-fms. The foreign body giant cells around cholesterol clefts in inflamed odontogenic keratocysts revealed more macrophage-like characteristics than the foreign body giant cells resorbing keratin pearls in squamous cell carcinomas. As such, both cases of foreign body giant cell exhibited immunoreactivity for the macrophage markers, such as CD14, RANK, and c-fms, yet only the latter case exhibited immunoreactivity for the osteoclast markers, such as CT-R and c-Src. Moreover, both cases of foreign body giant cells were positive for TRAP activity, yet negative for Cathepsin K activity. In contrast, the other inflammatory giant cells, Langhans’ giant cells, exhibited immunoreactivity for both the macrophage and osteoclast markers, yet were negative for TRAP activity. Meanwhile, the giant cells in the central giant cell granulomas reacted positively to both the macrophage and osteoclast markers, and were also positive for TRAP activity. Accordingly, these findings suggest that the immunoprofiles of giant cells in oral lesions vary according to the nature of the lesion, despite shared osteoclast and macrophage characteristics. Furthermore, the giant cells in tumorous lesions closely associated with bony destruction revealed more osteoclastic characteristics and their enzyme components were different according to the nature of the lesion