Changes in CD4⁺ T-cell surface marker phenotype and antigen receptor (TCR) repertoire were examined during the course of HIV infection and following therapy. A preferential decline in naive CD4⁺ T cells was noted as disease progressed. Following protease inhibitor therapy, naive CD4⁺ T cells increased only if they were present before initiation of therapy. Disruptions of the CD4⁺ TCR repertoire were most prevalent in patients with the lowest CD4⁺ T-cell counts. Antiviral or IL-12 therapy-induced increases in CD4⁺ T-cell counts led to only minor changes in previously disrupted repertoires. Thus, CD4⁺ T-cell death mediated by HIV-1 infection may result in a preferential decline in the number of naive CD4⁺ T cells and disruptions of the CD4⁺T-cell repertoire that are not immediately corrected by antiviral or immune-based therapies.