The regional distribution and cellular localization of insulin-degrading enzyme (IDE) was studied in adult human brain and pituitary by means of immunhistochemistry. We show that the enzyme is widely but unevenly distributed in human brain, with hypothalamic neurons showing the strongest immunoreaction. Strong to moderate immunostaining for the enzyme was observed in multiple cortical areas, hippocampus, cerebellum, and brain stem. Cellularly, IDE was mainly confined to neurons, but it was also present in oligodendrocytes, choroid plexus, and some blood vessel endothelial cells. A strong immunoreaction was seen in a subset of adenohypophysial cells. Some immunolabeling was also present in the neurohypophysis. The putative importance of the distribution of the enzyme in brain and pituitary is discussed in relation to its main known substrates, insulin, Abeta, and beta-endorphin.