Statement of the Problem: Macrophages are the target of attention in numerous diseases. Many studies reported them as the regulators of the growth, dissemination, and clinical behavior of various lesions. There are relatively scarce data regarding the role of macrophages in oral lesions, particularly odontogenic lesions.Purpose: This study investigated the macrophage density in odontogenic lesions of diverse biologic performance.Materials and Method: In this comparative analytical study, 60 cases of odontogenic lesions including ameloblastoma, keratocystic odontogenic tumor, dentigerous cyst, and radicular cyst were immunohistochemically stained with anti-CD68 antibody. One-way ANOVA and Tukey's HSD test were used for statistical analysis.Results: The results showed that the macrophage density in keratocystic odontogenic tumor (35.72±7.74) and ameloblastoma (46.12±9.84) was not significantly different from that in dentigerous cyst (43.87±8.13). Interestingly, the macrophage density in keratocystic odontogenic tumor was lower than that in dentigerous cyst. No significant difference was observed in macrophage density between the ameloblastoma and much less aggressive lesions like dentigerous cyst (p= 0.59). Macrophage density in radicular cyst (81.53±11.04) was significantly higher than other odontogenic lesions (p< 0.001).Conclusion: The lack of significant differences in macrophage density between the known aggressive odontogenic tumors and much less aggressive lesions implied that macrophages might not contribute to the biological behavior of the odontogenic lesions. Therefore, it could support the notion that targeted therapy would not have prominent clinical potential to decrease the extent of mutilating surgeries in odontogenic lesions.