OBJECTIVE To determine changes in the central endothelium and thickness of grafted corneas, and the cumulative probability of developing glaucoma, graft rejection, and graft failure 15 years after penetrating keratoplasty. METHODS In a longitudinal cohort study of 500 consecutive penetrating keratoplasties by one surgeon, regrafted eyes, fellow eyes of bilateral cases, and patients not granting research authorization were excluded, leaving 388 grafts for analysis. At intervals after surgery, we photographed the endothelium and measured corneal thickness by using specular microscopy. The presence of glaucoma, graft rejection, and graft failure was recorded. RESULTS The 67 patients examined at 15 years represented 30% of the available clear grafts (107 patients had died, 76 grafts had failed). Endothelial cell loss from preoperative donor levels was 71 +/- 12% (mean +/- SD, n = 67), endothelial cell density was 872 +/- 348 cells/mm2, and corneal thickness was 0.59 +/- 0.06 mm. Endothelial cell density was unchanged between 10 and 15 years (minimum detectable difference was 96 cells/mm2, alpha = .05, beta = .20, n = 54), whereas corneal thickness increased (P = .001, n = 55). The mean annual rate of endothelial cell loss from 10 to 15 years after surgery was 0.2 +/- 5.7% (n = 54). The cumulative probability of developing glaucoma, graft rejection, or graft failure was 20%, 23%, and 28%, respectively, and six of the eight graft failures after 10 years resulted from late endothelial failure. CONCLUSIONS From 10 to 15 years after penetrating keratoplasty, the annual rate of endothelial cell loss was similar to that of normal corneas, corneal thickness increased, and late endothelial failure was the major cause of graft failure.