Cellular factors that may protect against human immunodeficiency virus (HIV) infection were investigated in 27 HIV-exposed seronegative (ESN) female sex workers (FSWs) and 27 HIV-seronegative female blood donors. Compared with blood donors, ESN FSWs had significantly decreased expression levels of C-X-C chemokine receptor 4 (CXCR4), but not of C-C chemokine receptor 5, on both memory (P<.001) and naive (P=.041) CD4(+) T cells. CXCR4 down-regulation was associated with prolonged duration of commercial sex work by ESN FSWs. CD38 expression on CD8(+) T cells was significantly increased among ESN FSWs, compared with that among blood donors (P=.017). There were no differences in HLA-DR and CD62L expression between blood donors and ESN FSWs. Proportions of T cells producing the beta-chemokines RANTES (regulated on activation, normally T cell-expressed and -secreted), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta or the cytokines interleukin (IL)-2, IL-4, interferon-gamma, and tumor necrosis factor-alpha, were similar in the 2 groups. These data indicate that ESN FSWs differ from HIV-seronegative female blood donors with respect to immunological factors that have no clear protective potential against HIV transmission.