Summary Peripheral blood mononuclear cells ( PBMC ) of untreated, HIV ‐infected patients contain HIV ‐specific CD 8 T cells as well as their corresponding targets, HIV ‐infected CD 4 T cells. To determine if CD 4 T‐cell depletion in HIV ‐infected patients may result from autologous CD 8– CD 4 T‐cell interaction, CD 8 and CD 4 T cells procured from PBMC of acute and chronic untreated HIV ‐infected patients were sorted and co‐incubated. Formation of CD 8‐ CD 4 T‐cell conjugates was observed by fluorescence microscopy. Apoptosis of CD 4 T cells in conjugation was recorded by digitized images and was further observed and measured by FACS using Annexin staining. Perforin expression in the CD 8 T cells was measured using intracellular monoclonal perforin antibody staining. HIV DNA in the conjugated CD 4 T cells was detected by in situ PCR . We found that 6·1 ± 0·5% of CD 4 T cells from acute HIV ‐infected patients and 3·0 ± 0·5% from chronic HIV ‐infected patients formed CD 8– CD 4 T‐cell conjugates. Annexin binding and cell morphology typical of apoptosis were observed in the conjugated CD 4 T cells. The majority of CD 8 T cells that had conjugated to CD 4 T cells expressed perforin. The conjugated CD 4 T cells exhibited nuclear HIV DNA . CD 8 T cells and HIV ‐infected CD 4 T cells, both procured from the PBMC of untreated HIV ‐infected patients, form conjugates. Apoptotic lytic activity has been observed in the conjugated CD 4 T cells. We propose that CD 4 T‐cell annihilation in HIV ‐infected patients results, at least in part, from the interactions of perforin‐rich CD 8 T cells with autologous, HIV ‐infected CD 4 T cells.