Cells that are infected with HIV-1 were visualized at the mucosal surface of the nasopharyngeal and palatine tonsils in 14 specimens from patients with CD4+ T-cell counts of 200 to 900/microliter and 2- to 10-year histories of HIV-1 infection. Most of the cells with intracellular HIV-1 protein were small but multinucleated. The majority of these syncytia could be double labeled for HIV-1 RNA and a dendritic cell marker S100. In the palatine tonsil, the infected cells were not found in the stratified squamous epithelium that is adjacent to the pharynx. Instead, the S100+ infected syncytia were localized to the surface of tonsil invaginations or crypts. This mucosa, termed lymphoepithelium, contains antigen-transporting M cells that lie above regions where S100+ dendritic cells are juxtaposed with CD4+ lymphocytes. Likewise, infected cells were found in lymphoepithelium and not respiratory epithelium of nasopharyngeal tonsils or adenoids. We propose that lymphoepithelia, the histological term that describes the specialized regions where antigens access mucosa-associated lymphoid tissue, are sites where HIV-1 replication can be enhanced in syncytia derived from dendritic cells.