The immune response of human immunodeficiency virus (HIV)-exposed seronegative (ESN) women may be qualitatively different from that in those infected with HIV (HIV⁺). In a cohort of female commercial sex workers in Nairobi, Kenya, we found significantly lower (P ⩽ .01) levels of CD4⁺-specific immune activation and apoptosis in the ESN women compared with those in the HIV⁺ women. Compared with the HIV⁺ women, a lower proportion of the ESN women showed p24 peptide pool responses by the short-term, CD4⁺-specific, interferon (IFN)-γ intracellular cytokine staining assay, whereas the proportion showing responses by the long-term, CD8⁺-depleted T cell proliferation assay was similar. Interestingly, the ESN responders had a 4.5-fold stronger proliferation response (P = .002) than the HIV⁺ group. These data suggest that, compared with those in HIV⁺ women, CD4⁺ T cells in ESN women have a much greater ability to proliferate in response to p24 peptides.