Administration of interleukin 2 (IL-2) leads to selective and sustained CD4⁺ T-cell expansions in patients infected with HIV. It has been hypothesized that persistent CD4⁺ T-cell proliferation is the primary mechanism maintaining these expansions. T-cell proliferation was studied by ex vivo bromodeoxyuridine (BrdU) incorporation and intracellular Ki67 staining in HIV-infected patients treated with antiretroviral therapy (ART) with or without IL-2. In contrast to the tested hypothesis, HIV-infected patients treated with IL-2 had lower CD4⁺ T-cell proliferation compared to patients treated with ART alone. Independently of viral load changes, administration of IL-2 led to a decrease in basal CD4⁺ T-cell proliferation. Total numbers of CD4⁺ T cells with naive and recall, but not effector, memory phenotype were increased. The degree of CD4⁺ T-cell expansion correlated with the decreases in proliferation and a strong association was seen between these decreases and the expansion of the CD4⁺/CD25⁺ subset. Intermittent IL-2 in HIV-infected patients leads to expansions of CD4⁺/CD25⁺ T cells with naive and recall memory phenotypes that strongly correlate with decreases in proliferation. These data suggest that decreased T-cell proliferation is central in the CD4⁺ T-cell expansions induced by IL-2.