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Several independent observations suggest that cytotoxic T lymphocytes (CTL) are critical for the control of HIV infection. We have studied the adoptive transfer of CTL in three patients with aquired immunodeficiency syndrome (AIDS). In the first patient, we examined the CD8+ T cell repertoire before and after the transfer of syngeneic lymphocytes from his uninfected sibling to confirm whether aberrations exist in the CTL repertoire during advanced HIV infection and to determine whether adoptive immunotherapy with lymphocytes can lead to sustained expansions of CD8+ cells. Repertoire analysis revealed baseline expansions in some TCR subsets. Following cell transfer, there were new changes in two V-beta families, one at 24 hours post-infusion and the other and after 28 days, post-infusion. This study demonstrated that expansion and transient restoration of both CD4+ and CD8+ T-cells can occur in vivo following sygeneic cell transfer and that maximal lymphocyte expansion occurring appears to be maximal around 4 weeks postinfusion. In the second and third patients, we studied the adoptive transfer of HIV-specific CTL clones. Despite substantial HIV-specific lytic activity in vitro, there were no significant changes in the virus load of patients following adoptive transfer. In one patient, we traced the fate of an infused clone using soluble MHC-peptide complexes and showed that cells were rapidly eliminated within hours of infusion, probably through apoptosis. The use of CTL adoptive therapy in AIDS needs to be re-examined in light of these finding. Further trials of adoptive transfer of CTL should take into account the susceptibility of infused cells to in vivo apoptosis.