Purpose: There are conflicting results regarding the role of human leukocyte antigen (HLA) matching and ABO compatibility in corneal graft rejection for low- and high-risk patients. Lewis blood group antigens could be an important histocompatibility system. Beneficial effects of Lewis antigens matching have been reported in renal transplantation, but its effect is still unknown in corneal allografting. Methods: Between 1987 and 1993, ABO, Lewis and HLA phenotypes were determined in 697 consecutive grafts of corneal transplantations. The effect of Lewis matching on corneal endothelial rejection was evaluated over a 3-year period. Data analysis was done by plotting survival curves with the Kaplan-Meier method for survivorship data and performing statistical analysis with the log-rank test (Mantel-Haenszel test) for curve comparison. Results: In vascularized recipients, the ABO, Lewis, and HLA systems did not influence the graft outcome. However, for the unvascularized recipients, the endothelial 3-year rejection rate was significantly lower for both Lewis compatible patients (84% vs. 68%; log rank=0.03) and HLA compatible patients (86% vs. 72%; log rank=0.001), but not for the ABO-matched patients (82% vs. 79%; log rank=0.56). Conclusions: The authors' study suggests that Lewis antigens and HLA matching could positively influence corneal graft survival for the unvascularized recipients, but it did not seem to have any effect in vascularized recipients.