Background: The diverse clinical behavior of the odontogenic neoplasms remains indistinct and may be related to the surrounding microenvironment of these neoplasms. The immunohistochemical expression of CD163 and CD34 as elements of tumor microenvironment were evaluated in different odontogenic neoplasms of variable nature and correlate them with the tumor behavior.15 cases of benign odontogenic tumors, 15 locally aggressive odontogenic tumors, and 15 cases of malignant odontogenic neoplasms were investigated by immunohistochemistry. The count of the number of macrophages and blood capillaries in the stroma surrounding the tumor cells was detected in each section of the study groups. Results: Statistical analysis revealed a statistically significant difference between the studied groups regarding the count of macrophages expressing CD163 and blood capillaries expressing CD34 between benign, locally aggressive, and malignant neoplasms. A statistically significant positive correlation was detected by the Pearson Correlation test between both stains in the odontogenic neoplasms of variable nature and behavior. Conclusions: A positive link is observed between the increase in the number of M2 macrophages (expressing CD163) and microvessel density (expressing CD34) surrounding tumor cells; both elements are strongly related to the aggressiveness of the odontogenic neoplasms of variable nature.