The mechanism of CD4⁺ T cell depletion seen in HIV infection is largely mediated by increased apoptosis of these cells. The benefit of protease inhibitor (PI)-based antiretroviral therapy to CD4⁺ T cell recovery seems to involve more than its antiviral activity, and a direct antiapoptotic effect of PIs has been proposed to explain it. To test this hypothesis we have analyzed directly, ex vivo, the effects of two different highly active antiretroviral therapy (HAART) regimens on the levels of activation and apoptosis of T lymphocytes. A total of 126 subjects (43 receiving PIs, 35 receiving NNRTIs, 27 untreated HIV carriers, and 21 uninfected control subjects) was included in the study. Apoptosis was measured in blood lymphocytes by flow cytometry, using annexin V labeling. A broad panel of monoclonal antibodies was used to characterize the different CD4⁺ and CD8⁺ lymphocyte subsets. Apoptosis was significantly increased in HIV-untreated subjects, whereas apoptosis levels did not differ when comparing HIV-positive subjects undergoing HAART and uninfected control subjects. Likewise, markers of activation were elevated in HIV-positive untreated patients, and declined in subjects receiving treatment. However, activated-memory CD8⁺ T cells remained significantly higher in treated patients with respect to uninfected control subjects. No differences in the level of apoptosis or in immune activation markers were recognized when comparing subjects receiving PIs and those receiving NNRTIs. Antiretroviral therapy reduces apoptosis of CD4⁺ and CD8⁺ lymphocytes to normal levels without differences when comparing subjects receiving PI and NNRTI triple combinations. Despite complete suppression of viral replication, activated memory CD8⁺ T cells remain significantly elevated in subjects receiving HAART, suggesting the persistence of residual HIV replication. If PIs provide a positive effect on CD4⁺ counts beyond an antiviral effect, mechanisms other than apoptosis should be involved.