Immunohistochemical procedure (avidin biotin peroxidase complex) was applied in formalin-fixed and paraffin-embedded tissues obtained from 5 fatal cases of dengue infection associated with encephalopathy. Dengue virus antigen was demonstrated in the cytoplasm of phagocytic mononuclear cells from liver, spleen, and lung. Moreover, dengue viral antigens were here, to our knowledge, first demonstrated in the central nervous system (CNS) and numerous immunolabelled cells were found in brain sections from 3 cases. Extended immunohistochemical studies carried out in 1 case showed virus-positive cells mostly located within Virchow Robin space of medium size and small veins, infiltrating the white and grey matter, and often situated close to neurons displaying apparent cytopathic features. Furthermore, immunostaining for CD68 antigens demonstrated that most CD68+ macrophages and dengue antigen-positive cells share similar morphology and localization, suggesting a unique identity for at least part of these cells. Since in dengue fever, virus replicates mostly in cells of macrophage lineage, our results seem to indicate that infiltration of virus-infected macrophages could be one of the pathways by which viruses enter the brain in dengue encephalitis. Whether bone marrow-derived infected macrophages and viral-free particles induce CSN lesions through immune, metabolic, and/or direct viral-induced mechanisms will be essential to better understand the pathogenesis and provide new therapeutic strategies for dengue-associated encephalitis. As the evidence of tissue damage was nonspecific, the detection of virus antigen by immunoperoxidase technique appeared to be highly reliable for dengue diagnosis.