Purpose. It is controversial whether donor-recipient sex mismatch is a risk factor associated with corneal graft failure. The purpose of this study was to investigate the effect of sex mismatch on corneal graft failure in high-risk and non-high-risk patients. Design. A retrospective study. Methods. The medical charts of patients who underwent corneal transplantations by one surgeon between 2012 and 2017 were reviewed. Patients were defined as high-risk for failure if they had glaucoma, ocular surface disease, or corneal vascularization. Graft failure rates were compared using the Kaplan–Meier survival curves between sex matched and mismatched subjects and between male-to-female grafting and other patients. Results. One hundred and thirteen patients with a minimum follow-up of 18 months were included. In 62 non-high-risk patients, graft failure rates were similar between the sex mismatched and the sex matched recipients (p=0.645, log-rank) and in male donor to female recipient transplantations and in the other transplantations (p=0.496, log-rank). Analysis of fifty-one eyes of 51 high-risk graft recipients (mean age of 73.4 ± 12.7 years, N = 26 females) showed that graft failure rates were significantly higher in the sex mismatched than sex matched recipients (p=0.022, log-rank) and in male donor to female recipient transplantations than in the other transplantations (p=0.002, log-rank). Conclusions. Sex matching for every patient bares logistic difficulties; however, in patients who are at high-risk for graft failure, it may be a simple way to improve outcomes and better utilize corneal grafts.