Objective: To determine whether CD8+ cells inhibit HIV replication in vitro through the chemokines RANTES, macrophage inflammatory protein (MIP)-1α and MIP-1β. Design and methods: CD8+ T-cell clones were screened for their ability to inhibit HIV-1SF33 replication in CD4+ cells using p24 antigen and HIV RNA levels as endpoints. It has been suggested that such inhibition is mediated by three type cc chemokines: RANTES, MIP-1α and MIP-1β. To assess whether our T-cell clones inhibited HIV replication through a similar mechanism, the clones' ability to inhibit HIV-1SF33 replication was compared with their secretion of RANTES, MIP-1α and MIP-1β. Moreover, we tested the effects of neutralizing antibodies (NAb) against these factors on the anti-HIV-1SF33 activity of our clones as well as the direct effect of these recombinant cc-chemokines on HIV-1SF33 replication. Results: The CD8+ T-cell clones tested differed by their capacity to inhibit HIV-1 replication. We showed no correlation between the ability of these clones to secrete RANTES, MIP-1α and MIP-1β and their ability to repress HIV-1SF33 replication. In addition, this inhibitory activity against HIV-1SF33 could not be blocked by NAb directed against these chemokines, nor could these chemokines significantly inhibit HIV-1SF33 replication in acutely infected CD4+ cells in vitro. Conclusion: The data indicate that CD8+ cells can inhibit HIV-1SF33 replication in vitro by mechanisms that do not involve either cytotoxicity or RANTES, MIP-1α and MIP-1β