CD4⁺ T cells are thought to be critical in the maintenance of virus-specific CD8⁺ cytotoxic T-cell (CTL) responses. In human immunodeficiency virus type 1 (HIV-1) infection, a selective decline in HIV-1-specific CTL as the CD4⁺ T-cell count decreases has been reported. Using HLA-peptide tetrameric complexes, we show the presence at high frequency of HIV-1- and cytomegalovirus-specific CD8⁺ T cells when the peripheral CD4⁺ T-cell count was low or zero in three HIV-1-infected patients. No direct virus-specific CD8⁺-mediated effector activity was seen in these subjects, suggesting antigen unresponsiveness, although tetramer-sorted cells could be expanded in vitro in the presence of interleukin-2 into responsive effector cells. Thus, virus-specific CD8⁺ T cells can be maintained in the peripheral circulation at high frequency in the absence of circulating peripheral CD4⁺ T cells, but these cells may lack direct effector activity. Strategies designed to overcome this antigen unresponsiveness may be of value in therapies for the treatment of AIDS.