Immune activation has been suggested to increase susceptibility to human immunodeficiency virus type 1 (HIV-1) transmission, while at the same time it could be deemed essential for mounting an effective antiviral immune response. In this study, we compared levels of T cell activation between exposed seronegative (ESN) partners in HIV-1 discordant couples and HIV-unexposed control subjects in Dakar, Senegal. ESN subjects showed lower levels of CD38 expression on CD4(+) T cells than did control subjects. However, this was found to be associated with concurrent differences in the use of condoms: ESN subjects reported a higher degree of condom use than did control subjects, which correlated inversely with CD38 expression. In addition, we observed markedly higher levels of T cell activation in women compared with men, irrespective of sexual behavior. These findings question the relevance of low-level CD4(+) T cell activation in resistance to HIV-1 infection and underscore the need to take gender and sexual behavior characteristics of high-risk populations into account when analyzing correlates of protective immunity.