HAART in HIV-1-infected individuals has a broad spectrum of clinical outcomes. In the majority of patients, plasma viral load becomes undetectable and CD4+ T-cells increase over time. However, in a number of subjects a discrepancy between plasma viral load and the CD4+ T-cell recovery is observed. CD4+ T-cell count can rise despite persistently detectable plasma viral load (virologic nonresponders), or conversely does not increase despite full plasma viral load suppression (immunologic nonresponder). Defective immune reconstitution may depend on several factors including previous therapeutic failure, duration of antiretroviral therapy, low CD4+ T-cell count at the initiation of HAART, advanced stage of disease, low adherence to HAART, and previous treatment interruption. There is no definitive evidence that age, viral strain/clade, or host genetic factors play a role in these different responses to HAART. The roles of T-cell subsets, thymic function, and cytokines have been investigated. The increased T-cell activation/apoptosis has been associated with a lack of effective immunologic response. Unabated virologic replication in lymphoid tissues, despite undetectable plasma viral load, has been proposed as the underlying mechanism of cellular activation. However, this "paradoxical response" probably can be associated with other events. Insufficient CD4+ T-cell repopulation of lymphoid tissues may be due to a thymus failure or a defect in bone marrow function. Lifelong infection, the toxic effect of antiviral drugs on T- and B-cell precursors, the stage of disease, and the low number of CD4+ T-cells before HAART may also account for thymus exhaustion and insufficient T-cell renewal. Finally, an imbalance in the production of cytokines such as TNF, IL-2 and IL-7 may also be a crucial event for the induction of immune system failure. In patients in which CD4+ T-cells are not increased by HAART, therapeutic strategies aimed at increasing these cells and reducing the risk of infections are needed. IL-2 and/or other cytokines may be of benefit in this setting. Some antiviral drugs may be better than others in immunologic reconstitution. Protease inhibitors may have additional, independent positive effects on the immune system. On the other hand, there may be little rationale for using immunosuppressive agents such as cyclosporine or hydroxyurea in this subgroup of immunologic nonresponder patients, as these molecules may increase T-cell decline and/or favor susceptibility to infections.