Functional impairment of HIV-specific CD4+ T cells during chronic HIV infection is closely linked to viral replication and thought to be due to T cell exhaustion. Programmed death 1 (PD-1) has been linked to T cell dysfunction in chronic viral infections, and blockade of the PD-1 pathway restores HIV-specific CD4+ and CD8+ T cell function in HIV infection. This study extends those findings by directly examining PD-1 expression on virus-specific CD4+ T cells. To investigate the role of PD-1 in HIV-associated CD4+ T cell dysfunction, we measured PD-1 expression on blood and lymph node T cells from HIV-infected subjects with chronic disease. PD-1 expression was significantly higher on IFN-γ-producing HIV-specific CD4+ T cells compared with total or CMV-specific CD4+ T cells in untreated HIV-infected subjects (p= 0.0001 and p< 0.0001, respectively). PD-1 expression on HIV-specific CD4+ T cells from subjects receiving antiretroviral therapy was significantly reduced (p= 0.007), and there was a direct correlation between PD-1 expression on HIV-specific CD4+ T cells and plasma viral load (r= 0.71; p= 0.005). PD-1 expression was significantly higher on HIV-specific T cells in the lymph node, the main site of HIV replication, compared with those in the blood (p= 0.0078). Thus, PD-1 expression on HIV-specific CD4+ T cells is driven by persistent HIV replication, providing a potential target for enhancing the functional capacity of HIV-specific CD4+ T cells.