Tissue transglutaminase is an intracellular enzyme without established physiological function. Biochemically it can be detected in all organs, but no systematic in situ localization has been carried out so far. Here we report the immunohistochemical localization of transglutaminase in human tissues using an affinity purified, monospecific anti-human transglutaminase antibody. It is shown that the widespread organ distribution of the enzyme is the consequence of its occurrence in ubiquitous cell types such as endothelium and smooth muscle cells. Some organ-specific cell types express the enzyme constitutively (mesangial cells, renomedullary interstitial cells, thymic subcapsular epithelium, colonic pericryptal fibroblasts), while in others it seems to be induced either by external stimuli (epithelium of the female breast) or as part of their differentiation/maturation program (developing nephrons, enterocytes of the small intestine). The presence of tissue transglutaminase can be demonstrated in derivatives of all germ layers and in the trophoblast. The functional implications of these findings are presently unknown; however, based on its distribution the role of this enzyme in compartmentation and preservation of tissue integrity against stress may be suggested.