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To assess immunological parameters, including markers of immune activation, in highly HIV-1-exposed uninfected (EU) Vietnamese intravascular drug users (IDUs) in comparison with HIV-1-infected IDUs and HIVunexposed controls, we determined peripheral lymphocyte phenotypes in fresh whole blood samples from 32 EU IDUs, 28 HIV⁺ IDUs, and 26 blood donors. We found higher levels of activation markers (CD38, HLADR) on CD4⁺ and CD8⁺ T cells, lower percentages of naive CD4⁺ and CD8⁺ T cells, higher percentages of CD8⁺ T cells and of CD8⁺ T cells expressing CD25, and lower levels of CXCR4⁺CD4⁺ T cells in EU IDUs than in unexposed controls. Despite several differences in CD4⁺ and CD8⁺ T cell subset phenotypes, both EU and HIV⁺ IDUs exhibited a pattern of peripheral immune activation. Lymphocyte activation in EU IDUs may reflect immune stimulation driven by viral infections other than HIV-1 and/or allogeneic stimulation associated with needle sharing. Our results suggest that immune activation does not necessarily favor HIV-1 transmission, but, on the contrary, may alter the susceptibility of EUs to HIV-1 infection and contribute to their resistance.