Background: This study describes the histopathological, immunohistochemical (IHC) and in situ hybridization (ISH) data of 25 cases of oral ulcers in HIV-positive patients, with clinical and microscopical features similar to ulcers not otherwise specified (NOS)/necrotizing ulcerative stomatitis (NUS). Methods: Sex, age and clinical history were obtained from the clinical records. Histological analysis for H&E, Gomori-Grocott and Ziehl-Neelsen stains, IHC analysis to detect infectious agents and to characterize inflammatory cellular infiltrate, and ISH for cytomegalovirus (CMV) and EBER1/2 were performed. Results: Twenty-one patients were men and four were women (mean age of 34.6 years). The tongue was preferentially affected. Microscopically, the lesions showed extensive necrosis, leukocytoclasia, vasculitis with luminal fibrin clots and an intense inflammatory cellular infiltrate predominated by CD68 + atypical large cells, normal-sized and crescent-shaped nuclei macrophages, interspersed by CD8+ T lymphocytes. Mast cells were also observed in all samples studied. CD4+ T lymphocytes, CD20 + B lymphocytes and VS38c+ plasma cells were practically absent. CMV and EBER1/2 were identified in scarce cells of 3 and 16 of 25 cases respectively. Conclusion: These results show that CD68+ macrophages, followed by CD8+ T lymphocytes, were the predominant inflammatory cells, indicating they are relevant to the pathogenesis of the ulcers, possibly reflecting an abnormal immune response in the oral mucosa. The clinicopathological and immunoprofile features of the present cases are similar to NOS ulcers/NUS in HIV-positive patients. © 2008 The Authors.