Clonal expansion of activated T cells is controlled by homeostatic mechanisms leading to cell death of a large proportion of the cells. The CD3/TcR pathway induces cell death, mostly when triggered in the absence of costimulatory signal. The unique T cell–specific chemokine of the C class, lymphotactin (Lptn), has recently been shown to inhibit the production of Th1-type lymphokines in human CD4⁺ T cells. The present study shows the ability of Lptn to costimulate the death of CD4⁺ T lymphocytes triggered through CD3/TCR. The Lptn-mediated increased cell death exhibited characteristic features of apoptosis, as mainly determined by DNA fragmentation and exposure of an apoptotic-specific mitochondrial antigen. This apoptosis was dependent on Fas/FasL signaling, was not rescued by addition of interleukin 2, and proceeded with a predominant processing of both initiator procaspase-9 and effector procaspase-7. These caspase activities were further evidenced by specific cleavage of poly(ADP-ribose) polymerase (PARP) and CD3/TCR ζ-chain, but not DNA fragmentation factor (DFF45). This study demonstrates that the functional repertoire of Lptn in the regulation of human CD4⁺ T-lymphocyte activation includes the ability to costimulate apoptosis.