Background: Giant cell granulomas of the jaws are lesions that arise either peripherally in periodontal ligament and mucoperiosteum or centrally in the bone. The aim of this study was to evaluate expression of tartrate‐resistant acid phosphatase (TRAP) and CD163 proteins in multinucleated giant cells and mononuclear cells and compare proliferative activity between central giant cell granuloma (CGCG) and peripheral giant cell granuloma (PGCG) by immunohistochemistry of PCNA. Methods: The study was conducted on 40 formalin fixed paraffin embedded tissue blocks (20 CGCG ,20 PGCG). Five micron thick sections were cut from the paraffin blocks; two for hematoxylin and eosin to confirm diagnosis, while three sections were prepared for the immunohistochemical detection of TRAP, CD163 and PCNA by using Avidin-Biotin complex according to the manufacturer's instructures. Results: There was statistically significant difference regarding CD163 between CGCG and PGCG, while there was no statistically significant differences of TRAP and PCNA between CGCG and PGCG. Also, there was high negative correlation between immunoexpression of TRAP and CD163 in CGCG and PGCG. There was no correlation between TRAP and PCNA and between CD163 and PCNA. Conclusions: From the findings of the present study, it can be concluded that the histogenesis of MNGs of CGCG and PGCG was suggested to be of the osteoclastic origin, while there was no differences between proliferative activity between these two lesions.