To investigate the effect of HIV‐specific CD8⁺ T cells on viral plasma load and disease progression, we enumerated HLA‐A2‐, B8‐ and B57‐restricted CD8⁺ T cells directed against several HIV epitopes in a total of 54 patients by the use of tetrameric HLA‐peptide complexes. In patients with high CD4⁺ T cell numbers, HIV‐specific tetramer⁺ cells inversely correlated with viral load. Patients with CD4⁺ T cell numbers below 400/μ l blood, however, carried high viral load despite frequently having high tetramer⁺ T cell numbers. This lack of correlation between viral load and tetramer⁺ cells did not result from viral escape variants, as in only 4 of 13 patients, low frequencies of viruses with mutated epitopes were observed. In 15 patients we measured CD8⁺ T cell antigen responsiveness to HIV peptide stimulation in vitro. FACS analyses showed differential IFN‐γ production of the tetramer⁺ cells, and this proportion of IFN‐γ‐producing tetramer⁺ cells correlated with AIDS‐free survival and with T cell maturation to the CD27^– effector stage. These data show that most HIV‐infected patients have sustained HIV‐specific T cell expansions but many of these cells seem not to be functional, leaving the patient with high numbers of non‐functional virus‐specific CD8⁺ T cells in the face of high viral burden.