Recent data provide evidence that antigen-specific CD4+ T-cell clones or antigen-activated T-cell lines can kill antigen-presenting cells (APC). We focused our studies on monocytes acting as APC in cultures of T cells freshly isolated from peripheral blood. The presence of monocytes in culture was monitored by their ability to emit light during phagocytosis of latex particles (latex-induced chemiluminescence). Using this approach as well as flow cytometry, evidence is presented that monocytes are eliminated from cultures with T cells activated with recall antigens (PPD or TT). The mechanism of monocyte elimination involved apoptosis as judged from in situ detection of DNA strand breaks by the terminal deoxynucleotidyl transferase assay. The antigen- but not lectin-dependent monocyte elimination was MHC-restricted and mediated by CD4+ T lymphocytes. This finding supports the hypothesis that elimination of APC is a general phenomenon during T-cell activation and may represent an important immunoregulatory mechanism.