Intramembrane changes occurring in dysfunctional corneal endothelial cell membranes were examined using freeze-fracture and transmission electron microscopy techniques. Three categories of dysfunctional endothelium were examined: aphakic bullous keratopathy, pseudophakic bullous keratopathy and Fuchs' endothelial dystrophy. Keratoconus corneas and a donor eye bank eye were examined as normal controls. Four intramembrane changes were observed on replicas of freeze-fractured membranes in each category of dysfunctional endothelium. These were a marked reduction in intramembrane particle density on lateral membranes, altered apico-lateral junctional complexes, increased vesicle fusion sites on apical, lateral and basal membranes, and abnormal desmosome-like particle aggregates on the lateral endothelial cell membranes. The marked reduction in intramembrane particles on lateral membranes may be due to a change in the macromolecular components associated with pump dysfunction. The increase in membrane vesicle fusion sites and the breakdown in intercellular junctions may be associated with increased permeability during barrier dysfunction.