We identified all patients who had undergone penetrating keratoplasty for keratoconus and were being observed longitudinally (N = 174). During the follow-up period, 57 of 174 patients (33%) showed evidence of an allograft rejection episode, which occurred at an average of eight months after the operation. We analyzed specular photographs of the corneal endothelium, taken before and after the first allograft rejection episode. A significant decrease in endothelial cell density was observed (11.8%, P less than .0001). As a control, we analyzed all available specular photographs from patients with keratoconus who showed no evidence of allograft rejection after penetrating keratoplasty. The observed endothelial cell density decrease (11.8%) in patients with keratoconus undergoing allograft rejection exceeded that found in the control subjects (6.8%) during a comparable time period (P = .06). Severe allograft rejection episodes resulted in a decrease in endothelial cell density that exceeded expected loss significantly (14.8% compared with 6.9%, P = .01), whereas mild allograft rejection episodes were not associated with a loss in endothelial cell density exceeding that expected (1.8% compared with 6.5%, P = .34).