In progressive viral infection, antiviral T cell function is impaired by poorly understood mechanisms. Here we report that the inhibitory immunoregulatory receptor CTLA-4 was selectively upregulated in human immunodeficiency virus (HIV)–specific CD4⁺ T cells but not CD8⁺ T cells in all categories of HIV-infected subjects evaluated, with the exception of rare people able to control viremia in the absence of antiretroviral therapy. CTLA-4 expression correlated positively with disease progression and negatively with the capacity of CD4⁺ T cells to produce interleukin 2 in response to viral antigen. Most HIV-specific CD4⁺ T cells coexpressed CTLA-4 and another inhibitory immunoregulatory receptor, PD-1. In vitro blockade of CTLA-4 augmented HIV-specific CD4⁺ T cell function. These data, indicating a reversible immunoregulatory pathway selectively associated with CD4⁺ T cell dysfunction, provide a potential target for immunotherapy in HIV-infected patients.