Persistent HIV infection results in a decrease in absolute counts of CD4(+) CD25(+) regulatory T cells (Treg). To investigate the role of decreased Treg counts in the regulation of excessive activation and apoptosis of CD8(+) T cells in human immunodeficiency virus (HIV)-1 infection, we characterized Treg in 83 HIV-1-infected individuals, including 19 long-term non-progressors (LTNPs) and 51 typical progressors (TPs) who were treatment-naïve, and 13 AIDS patients on highly active antiretroviral therapy (HAART), of whom nine were complete responders (CRs) and the remaining four were non-responders (NRs) to the treatment. TPs but not LTNPs had a significant decrease in absolute counts of circulating Treg, which was inversely correlated with the activation and apoptosis of CD8(+) T cells. Efficient HAART was found to increase Treg counts in CR patients and temper the excessive activation and apoptosis of CD8(+) T cells. Moreover, isolated Treg significantly inhibited the spontaneous and anti-CD3-induced apoptosis of CD8(+) T cells in a dose-dependent manner in vitro. Thus, our findings indicate that the decrease in Treg closely correlates with the increase in apoptotic CD8(+) T cells and disease progression in chronic HIV-1 infection, and that Treg may play a key role in maintaining the balance between the amount and quality of CD8(+) T cells in HIV-1 infection. Manipulation of Treg function may be a promising strategy for immune therapy of this disease.