The adenosine 5'-triphosphate (ATP)-gated P2X₇-receptor (P2X₇-R) is predominantly expressed in macrophages, and it is thought to play a key role in inflammatory cytokine signaling through activation of caspase-1 (casp1; also known as IL-1b converting enzyme). Typically, 15–20 min P2X₇-R stimulation in lipopolysaccharide (LPS)-primed macrophages is required to elicit casp1-dependent pro-IL-1b processing and release of bioactive IL-1b. However, prolonged P2X₇-R stimulation is known to induce cell death, suggesting that the window for inflammatory cytokine signaling without cell death is narrow. Here, we tested whether brief (2–4 min) P2X₇-R activation was sufficient to induce delayed apoptosis. That is, we hypothesized that induction of apoptosis is the foremost function of P2X₇-R stimulation. We isolated resident peritoneal macrophages from mice and loaded them with the novel caspase-3/7 probe DEVD-NucView488, which is membrane permeable and non-fluorescent until DEVDase (caspase-3/7) activity is switched on. Indeed, we found that brief stimulation of P2X₇-Rs led to delayed (hours) caspase-3/7 activity and apoptotic cell death. LPS-priming was not a pre-requisite for P2X₇-induced delayed apoptosis. Microblebbing, mitochondrial membrane depolarization and phosphatidylserine flip were early events (within minutes) of P2X₇-R stimulation. P2X₇-induced apoptotic signaling was still observed in macrophages isolated from casp1-/- mice, but it was absent in P2X₇-deficient macrophages. Bracketing the P2X₇-R stimulation with Ca²⁺-free medium was protective against apoptosis. Thus, our data show that the P2X₇-R is essentially a death receptor for macrophages.