To better understand the cutaneous immune response to Treponema pallidum, we performed an immunohistologic study of skin biopsies from a total of 11 patients with secondary syphilis; biopsies from five persons infected with HIV-1 were included in the analysis to assess at the tissue level the impact of concomitant HIV-1 infection on disease expression. In all of the biopsies, staining for HLA-DR, a marker for cellular activation, was observed among infiltrating leukocytes, dermal vascular endothelial cells, and keratinocytes. Infiltrating mononuclear cells stained positively for CD4 or CD8, with CD4+ cells always being in the majority. Surprisingly, most of the CD4+ cells had histiocytic, rather than lymphocytic, morphologic characteristics. Immunostaining for CD14 confirmed that these cells were monocytic in origin, whereas immunostaining for CD3 revealed that the lymphocytes were predominantly CD8+ cytotoxic T cells. B cells were not detected despite the presence of variable numbers of plasma cells in all specimens. By immunofluorescence, all of the specimens demonstrated perivascular deposition of immunoglobulins, complement, or fibrinogen; linear staining at the dermal-epidermal junction also was observed in most of the specimens. No differences in immunocytochemical or immunofluorescence staining patterns were observed between the specimens from patients who were HIV positive and patients who were HIV negative. In addition to providing a more precise definition of the infiltrating cells in syphilitic lesions, our results, taken as a whole, indicate that cellular immune processes are largely responsible for the development of cutaneous manifestations during syphilitic infection and that coinfection with HIV-1 has little discernible effect on the cutaneous response to T. pallidum.