Aim: Peripheral giant cell granuloma (PGCG) and central giant cell granuloma (CGCG) of the jaws are benign proliferations of spindle-shaped mesenchymal cells and multinucleated giant cells. Despite the histopathologic similarities, they have markedly different clinical behavior. PGCG shows low recurrence rate whereas CGCG shows a variable clinical behavior ranging from nonaggressive lesions to aggressive lesions characterizing by pain, rapid growth, and high recurrence rate. Therefore, the aim of the study was to compare CGCG with PGCG by immunohistochemistry using Ki-67, osteopontin (OPN), and integrin alpha(v) antibodies. Subjects and Methods: Twenty PGCG and 20 CGCG were selected for immunohistochemical evaluation of OPN, integrin alpha(v), and Ki-67 in multinucleated giant cells and mononucleated cells of PGCG and CGCG. Results: PGCG showed higher Ki-67 immunoreactivity in mononucleated cells compared to CGCG (P < 0.05). There was no reactivity with Ki-67 in multinucleated giant cells of both groups. Mononucleated cells in CGCGs demonstrated increased OPN and integrin alpha(v) expressions in comparison with PGCGs (P < 0.05). Conclusions: The clinic behavior of CGCG being more aggressive than PGCG might be explained by the high expression of OPN and integrin alpha(v). Further studies are necessary to evaluate the other OPN receptors and their role on the biologic behavior of these lesions.