Co-signaling molecules have been demonstrated to regulate regulatory T cells’ (Tregs) function during human immunodeficiency virus (HIV) infection. A recently reported co-signaling molecule called herpes virus entry mediator (HVEM), a member of the tumor necrosis factor receptor family, can both enhance and inhibit the immune response. HVEM was also reported to enhance the suppressive function of regulatory T cells in mice. However, it remains unknown whether HVEM can regulate Treg function in HIV-infected patients or whether HVEM affects HIV disease progression. In this study, we found that the blockage of the HVEM could weaken Tregs’ suppressive activity to effector T cells (Teffs). HVEM expression is reduced during the asymptomatic phase of HIV infection and fairly predictive of the recovery of CD4+T-cells in response to highly active anti-retroviral therapy (HAART), more so than nadir CD4+T-cell count or viral load. Taken together, these findings demonstrate the importance of HVEM in relation to Treg function and HIV disease progression, which would have therapeutic implications and provide insight into the pathogenesis of acquired immune deficiency syndrome (AIDS).