BACKGROUND Although the determinants of immune deficiency and immune restoration in chronic human immunodeficiency virus (HIV)-1 infection are not well understood, immune activation has been proposed as being central to the pathogenesis of HIV. METHODS A randomized, controlled trial of cyclosporin A treatment for 2 weeks was performed in persons with chronic HIV-1 infection who were beginning a standardized antiretroviral therapy (ART) regimen. RESULTS Treatment with cyclosporin A provided only a marginal and transient enhancement in circulating T cell restoration that was largely restricted to cells expressing the CCR7 chemokine receptor and that did not persist beyond 2 weeks. CONCLUSIONS Cyclosporin A coadministered for 2 weeks with ART provided no sustained immunologic benefit to persons with chronic HIV-1 infection. If immune activation drives progressive immune deficiency in chronic HIV-1 infection, these activation pathways may not be sensitive to cyclosporin.