Antiretroviral therapy in human immunodeficiency virus infection is occasionally associated with poor immunologic responses despite full suppression of viral replication. As some combinations of nucleoside analogues (NA) have been associated with paradoxical depletion of CD4+ T- cells, we postulated that depleting the antiretroviral regimen of NAs would improve quantitative immunological parameters. In a longitudinal prospective study we quantified CD4+ Tcells after removing NAs from antiretroviral therapy. The NA for regimen consisted of atazanavir (300mg qd), saquinavir (1000mg bid), and ritonavir (100mg qd) in 14 patients with immunologic failure despite undetectable plasma HIV-RNA (CD4+ T-cells < 250 cells/μL ( < 17%) HIV RNA, < = 50 copies/mL). Additionally, we assessed the state of immunologic activation markers (CD38+HLA-DR+ on CD4+ and CD8+ T-cells) by flow cytometry. The regimen was well tolerated. During the 48 week study CD4+ T-cell counts improved significantly (mean and ± SEM [standard error of mean], baseline: 174/μL (12.4%) [15, 5.8%], week 24: 232/μL (14%) [26, 5.3%], week 48: 267/μL (15.4%) [34, 4.3%]) with preservation of full viral suppression (p < 0.05). Activation parameters of CD4+ T-cells, but not of CD8+ T-cells, decreased significantly. This treatment strategy may represent an option for patients with poor immunologic responses to antiretroviral therapy despite undetectable viremia.