Older age is a strong predictor of accelerated human immunodeficiency virus (HIV) disease progression. We investigated the possible immunologic basis of this interaction by comparing older (>/=45 years) and younger (</=30 years) HIV-infected adults with simultaneously enrolled, aged-matched, healthy volunteers. Cross-sectional comparisons suggested age-associated reductions in naive CD8(+) cells and in the expression of CD28(+) on CD8(+) cells among both HIV-infected subjects and control subjects. Opposite patterns of CD4(+) and CD8(+) cell differences were apparent between these subject groups. HIV infection, but not age, was associated with impairments in delayed-type hypersensitivity responses, lymphoproliferation, and spontaneous apoptosis and with alterations in expression of chemokine receptors CCR5 and CXCR4. Reduced thymic volumes were associated with age and with HIV infection among younger, but not older, subjects. Because of their common association with age and HIV disease, naive CD8(+) cell depletion, diminished CD28 expression on CD8(+) cells, and reduced thymic volumes are possible correlates of the interaction of age with HIV disease.