HSV-2 infection is common and generally asymptomatic, but it is associated with increased HIV susceptibility and disease progression. This may relate to herpes-mediated changes in genital and systemic immunology. Cervical cytobrushes and blood were collected from HIV-uninfected African/Caribbean women in Toronto, and immune cell subsets were enumerated blindly by flow cytometry. Immune differences between groups were assessed by univariate analysis and confirmed using a multivariate model. Study participants consisted of 46 women, of whom 54% were infected with HSV-2. T cell activation and expression of the mucosal homing integrin α4β7 (19.60 versus 8.76%; p< 0.001) were increased in the blood of HSV-2–infected women. Furthermore, expression of α4β7 on blood T cells correlated with increased numbers of activated (coexpressing CD38/HLA-DR; p= 0.004) and CCR5+(p= 0.005) cervical CD4+ T cells. HSV-2–infected women exhibited an increase in the number of cervical CD4+ T cells (715 versus 262 cells/cytobrush; p= 0.016), as well as an increase in the number and proportion of cervical CD4+ T cells that expressed CCR5+(406 versus 131 cells, p= 0.001; and 50.70 versus 34.90%, p= 0.004) and were activated (112 versus 13 cells, p< 0.001; and 9.84 versus 4.86%, p= 0.009). Mannose receptor expression also was increased on cervical dendritic cell subsets. In conclusion, asymptomatic HSV-2 infection was associated with significant systemic and genital immune changes, including increased immune activation and systemic α4β7 expression; correlation of the latter with highly HIV-susceptible CD4+ T cell subsets in the cervix may provide a mechanism for the increased HIV susceptibility observed in asymptomatic HSV-2–infected women.