To determine the relationship between corneal allograft rejection and failure, we studied patients who underwent penetrating keratoplasty for herpes simplex keratitis (n = 82) and keratoconus (n = 345), two frequent indications for keratoplasty in young patients, using survival analysis. For first grafts for herpes, the probability of survival was significantly less than it was for keratoconus (P less than 0.0001). For second grafts, this difference was less pronounced, and for three or more grafts, the difference in survival was not significant. The incidence of rejection episodes was similar in first grafts for herpes (16.6%) and keratoconus (18.5%) (P greater than 0.05). However, the incidence of rejection episodes in regrafts for herpes was significantly greater than in keratoconus (23.7 versus 17%, P less than 0.01). The incidence of failure after rejection episodes (first grafts and regrafts combined) was significantly greater in grafts for herpes (52.4 versus 16.2%, P less than 0.001). Because survival after multiple regrafts in both groups is poor, additional measures, such as tissue matching, may be necessary to improve the likelihood of success in these high-risk cases.