Oral papillomatosis represents a benign lesion of the oral mucosa often induced by human papillomavirus (HPV) or having a non-infection local or general etiology. HPVs are very well adapted and efficient viruses able to produce changes in the immune system, endowed with the ability to replicate in the keratinocytes and to remain silent. The natural evolution of HPV infection is different, depending on the efficiency of the innate immune system. The purpose of this study was to explore Toll-like receptor 9 (TLR9) immunohistochemical expression in low-risk (LR)-HPV oral infection and its ability to facilitate an efficient immune response by activating the macrophages, which serve as main antigen-presenting cells. Samples of two groups of oral mucosae – LR-HPV-positive and HPV-negative – were processed for immunohistochemistry technique and incubated with antibody against TLR9 and cluster of differentiation 68 (CD68). Image analysis and morphometry were conducted to assess the intensity of TLR9 immune signal in the epithelium and the number of macrophages labeled by CD68. We found a statistically significant difference between macrophage count for the subjects in HPV-positive and HPV-negative groups; thought no significant differences of TLR9 immune signal was noted, which demonstrates a diminished immune response in HPV-positive group, probably influencing the time of lesion’s clearance.