The normal human corneal endothelial monolayer maintains stromal water equll Ibrlum and thus, transparency, by means of a pump-leak mechanism (1-3). Water leaks into the stroma through non-tight lateral cell junctional complexes and is drawn out by an energy dependent cell membrane ion pump. We investigated the histochemical localization of cytochrome oxidase activity (CO), an important energy-deriving mitochondrial enzyme in dysfunctional corneas with Fuchs endothelial dystrophy (ED), which is a regionally distributed disease. Keratoconus corneas were used as controls for functional control endothelium. In the central area of the corneal button, decreased CO activity was demonstrated which correlated clinically with central corneal edema. This reflects decreased metabolic activity and/or decreased numbers of mitochondria in the attenuated dysfunctional cells. In the mid-periphery, CO activity was increased in the cellular rosettes surrounding guttata, which may be related to increased synthesis of abnormal Descemet's membrane and guttata. Peripherally, the large polygonal cells resembled functional endothelium in their morphology and CO activity. We have, therefore, demonstrated regional differences in energy metabolism in endothelium from Fuchs' ED patients which may be related to decreased numbers of mitochondria in the dysfunctional cells, and/or to synthesis of abnormal Descemet's membrane material.