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To measure endothelial cell and keratocyte densities in transplanted corneas and the changes in these densities with time.The endothelia of 500 consecutive penetrating corneal transplants were studied longitudinally by specular microscopy for 10 to 20 years. The keratocytes of 36 corneal transplants that varied in postoperative times from 1 month to 20 years were studied cross-sectionally by clinical confocal microscopy. The keratocytes of five transplanted corneas were studied longitudinally by confocal microscopy at 1 day, 1 week, and 1 month postkeratoplasty.Endothelial cell density decreased progressively at an accelerated rate for 20 years after transplantation, with concurrent increases in the coefficient of variation of cell area and corneal thickness and decreases in the percentage of hexagonal cells. Grafts with insufficient endothelial cells developed late endothelial failure, which was the primary cause of graft failure after the first 5 postoperative years. The grafts with late endothelial failure did not lose endothelial cells faster than grafts that did not fail, but instead had fewer cells immediately after transplantation, diminishing to a critically low cell density earlier. The keratocyte density was also decreased in transplanted corneas. Keratocytes became “activated” during the first week after keratoplasty and in grafts with late endothelial failure.It should be possible to prevent or delay late endothelial failure, the primary cause of graft failure, by increasing the number of endothelial cells on transplanted corneas. The status of the keratocytes appears to affect corneal transparency and, thus, visual quality in the grafted eye.