Mxi2 is one of three known alternative spliced forms of the stress-activated mitogen-activated protein kinase p38 (CSBP). Mxi2 was originally identified as a Max-interacting protein and is the smallest member of the family of stress-activated kinases isolated to date. Mxi2 lacks most of the XI domain found in p38 and instead has a distinct COOH-terminal sequence of 17 amino acids. Here we present the genomic structure of the Mxi2/p38 locus on human chromosome 6q21.2/21.3 and establish the origin of the three spliced forms of p38. Using Mxi2-specific antibodies in mouse organs, we found the Mxi2 protein to be present exclusively in the kidney. Mxi2 is present predominantly in the distal tubule of the nephron and the level of the protein decreased during kidney ischemia-reperfusion. Stress signals or other known activators of the p38 pathway including MAP kinase-kinase 3 and MAP kinase-kinase 6 did not induce the kinase activity of Mxi2 using ATF-2 as a substrate. With the use of hybrid proteins encoding different portions of Mxi2 and p38 polypeptides, the different properties of Mxi2 can be assigned to its unique COOH terminus.