BACKGROUND: Male circumcision reduces human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV-2) acquisition, and HSV-2 infection is associated with an increased risk of HIV acquisition. To assess the cellular basis for these associations, we estimated immunologic cellular densities in foreskin tissue. METHODS: Immunostained CD1a(+) dendritic cell and CD4(+) and CD8(+) T cell densities were quantified in foreskin samples obtained from medical circumcision in Rakai, Uganda (35 HIV- infected, HSV-2-infected men; 5 HIV-infected, HSV-2-uninfected men; 22 HIV-uninfected, HSV-2-infected men; and 29 HIV-uninfected, HSV-2-uninfected men. RESULTS: CD1A(+) dendritic cell densities did not vary by HIV or HSV-2 status. Compared with densities in HIV-uninfected, HSV-2-uninfected men (mean, 26.8 cells/mm(2)), CD4(+) T cell densities were similar in the HIV-infected, HSV-2-infected group (mean, 28.7 cells/mm(2)), were significantly decreased in the HIV-infected, HSV-2-uninfected group (mean, 11.2; P textless .05), and were increased in the HIV-uninfected, HSV-2-infected group (mean, 68.7; P textless .05). Dermal CD8(+) T cell densities were higher in the HIV and HSV-2-coinfected group (mean, 102.9) than in the HIV-uninfected, HSV-2-uninfected group (mean, 10.0; P textless .001), the HIV-infected, HSV-2-uninfected group (mean, 27.3; P textless .001), and the HIV-uninfected, HSV-2-infected group (mean, 25.3; P textless .005). DISCUSSION: The increased CD4(+) cellular density in the HIV-uninfected, HSV-2-infected men may help to explain why HSV-2-infected men are at increased risk of HIV acquisition. The absence of this increase in men coinfected with both HIV and HSV-2 is likely in part the result of the progressive loss of CD4(+) cells in HIV infection. Conversely, HIV and HSV-2 coinfection appears to synergistically increase CD8(+) T cell densities.