Failure of cytotoxic T lymphocytes (CTL) or natural killer cells (NK) to kill target cells by perforin/granzyme-induced apoptosis causes severe immune dysregulation. In familial hemophagocytic lymphohistiocytosis, perforin-deficient infants suffer a fatal ‘cytokine storm’ resulting from macrophage over-activation, but the link to failed target cell death is not understood. We show that prolonged target cell survival greatly amplifies the quanta of inflammatory cytokines secreted by CTL/NK cells and that interferon-y directly invokes the activation and secondary over-production of pro-inflammatory IL-6 from naïve macrophages. Further, using live cell microscopy to visualise hundreds of synapses formed between WT, perforin-null or granzyme A/B-null CTL/NK and their targets in real time, we show that hyper-secretion of interleukin-2, TNF, interferon-g and various chemokines is linked to failed disengagement of perforin- or granzyme-deficient lymphocytes from their targets, with mean synapse time increased five-fold, from ~8min to >40min. Surprisingly, the signal for detachment arose from the dying target cell and was caspase-dependent, as delaying target cell death with various forms of caspase-blockade also prevented their disengagement from fully competent CTL/NK cells and caused cytokine hyper-secretion. Our findings provide the cellular mechanism through which failed killing by lymphocytes causes systemic inflammation involving recruitment and activation of myeloid cells.