Interleukin (IL)-18 is an important proinflammatory cytokine processed and released from cells of the monocyte lineage by activation of the P2X 7 receptor by extracellular adenosine 5 0 -triphosphate (ATP). We examined if a loss-of-function polymorphism of the human P2X 7 receptor (glutamic acid-496 to alanine) impairs this process. Using a whole blood-based assay, ATP-induced release of IL-18 from homozygous subjects after 120 min incubation with ATP was 42% of that from wildtype subjects. Moreover, the level of ATP-induced IL-18 release from lipopolysaccharide (LPS)-primed monocytes of homozygous subjects after 30 and 60 min incubation with ATP was 21 and 44%, respectively, of that from wild-type monocytes. Nigericin, a K þ ionophore, induced a similar release of IL-18 from monocytes of either genotype. ATP-induced ethidium þ uptake in LPS-primed, monocytes of homozygous subjects was only 11% of that in wild-type monocytes, while P2X 7 surface expression on LPS-primed, homozygous monocytes was 44% of that on wild-type monocytes.