The human penile urethra contains numerous IgA and J chain-positive plasma cells, and the epithelium expresses secretory component, the transport molecule for polymeric IgA, indicating that this region is an active site of secretory IgA-mediated immune defense. At the distal tip, the mucosae of the meatus and fossa navicularis contain intraepithelial dendritic cells but few macrophages, whereas the urethra proper contains many macrophages within the lamina propria and epithelium, but no dendritic cells. T lymphocytes are abundant and ubiquitous in all regions of the urethra. Both CD8+ and CD4+ subpopulations of T lymphocytes are present in the lamina propria and epithelium, although CD8+ cells predominate. The majority of T lymphocytes are positive for CD45RO (memory marker), and many are also positive for the alpha E beta 7 integrin (mucosal-associated antigen). These data indicate that the human urethra is a highly dynamic immunocompetent tissue possessing all the necessary elements for antigen presentation and both humoral and cellular mucosal immune responses. Furthermore, the urethra resembles other mucosal surfaces in terms of lymphocyte subpopulations, segregation of phenotypes and expression of antigenic determinants characteristic of mucosal lymphocytes. It is likely that this region plays a dominant role in protecting the male urogenital tract against ascending infections, and should be targeted in vaccination strategies directed against sexually transmitted diseases.