Verruciform xanthoma (VX) is a rare, benign lesion, mainly found in the oral mucosa. Histologically and ultrastructurally, the lesion is characteristic and well defined. However, the etiology of the lesion remains unclear. The purpose of the present study was to elaborate upon the pathogenesis of VX by evaluation of an additional series of oral examples for human papillomaviruses (HPV), using immunohistochemistry and in situ hybridization, and to further characterize the cellular components of VX immunohistochemically. Twelve specimens diagnosed as VX were retrospectively collected. One of the twelve specimens was positive for HPV types 6/11 by in situ hybridization. None of the twelve specimens demonstrated the presence of HPV antigen by immunohistochemistry. By immunohistochemical studies, the predominant cells in the inflammatory infiltrate were T cells. The foam cells were of monocyte/macrophage lineage. S-100-positive (Langerhans) cells were occasionally found in the suprabasal layer of the epithelium. HLA-DR-positive keratinocytes were noted at the intense inflammatory sites. Taken together, these findings suggest that an immune response may play a role, at least in part, in VX pathogenesis.