We determined the cellular location of interleukin-18 (IL-18) and caspase-1 and the purinergic receptor P2X7, two proteins necessary for its activation and secretion. The mRNA and protein of IL-18 were detectable in normal human kidney by means of polymerase chain reaction (PCR), in situ hybridization, and Western blot. Immunohistochemistry located IL-18 to nephron segments containing calbinbin-D28k or aquaporin-2 that suggest location in the distal convoluted and the connecting tubule and to parts of the collecting duct. IL-18 was not detected in the thick ascending limb of Henle. Confocal microscopy showed that IL-18 was expressed in cells negative for calbindin-D28k and for aquaporin-2 but positive for the vacuolar H⁺-ATPase. This demonstrates that the intercalated cells produce IL-18. These segments were also positive for caspase-1 and P2X7 that are essential for IL-18 secretion. Our results show that IL-18 is constitutively expressed by intercalated cells of the late distal convoluted tubule, the connecting tubule, and the collecting duct of the healthy human kidney. Since IL-18 is an early component of the inflammatory cytokine cascade, its location suggests that renal intercalated cells may contribute to immediate immune response of the kidney.