Cytomegalovirus (CMV)-immune recovery was characterized in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy. CMV lymphocyte proliferation (LP), responder-cell frequency (RCF), and interferon (IFN)-gamma and interleukin (IL)-2 secretion were studied in CMV-seropositive HIV-infected patients and in CMV-seropositive HIV-uninfected control subjects. HIV-infected patients and control subjects had similar proportions of IL-2 and IFN-gamma, but levels were lower in HIV-infected patients. LP and RCF were significantly less frequent and of lower magnitude in HIV-infected patients. The measures of CMV cell-mediated immunity were correlated in HIV-uninfected but not in HIV-infected subjects. To investigate this, IL-2, IL-12, anti-CD28 plus anti-CD49d, or anti-IL-10 was added in vitro, with no effect on LP. However, CD8 cell depletion of mononuclear cells from HIV-infected patients increased LP responses to levels similar to those of uninfected control subjects; before depletion, only RCF correlated with CD4 cell counts, but after depletion, LP also correlated with CD4 cell counts.