To identify recipient factors that may be related to risk of corneal graft failure. Multicenter, prospective, double-masked, controlled clinical trial. One thousand ninety subjects undergoing corneal transplantation for a moderate-risk condition (principally Fuchs' dystrophy or pseudophakic corneal edema). Donor corneas were assigned using a random approach without respect to recipient factors, and surgeons were masked to information about the donor cornea, including donor age. Surgery and postoperative care were performed according to the surgeons' usual routines, and subjects were followed up for 5 years. Baseline factors were evaluated for their association with graft failure. Graft failure, defined as a regraft or a cloudy cornea that was sufficiently opaque to compromise vision for a minimum of 3 consecutive months. Preoperative diagnosis of pseudophakic or aphakic corneal edema increased graft failure risk approximately 4-fold compared with Fuchs' dystrophy (27% vs. 7%). Prior glaucoma surgery with preoperative glaucoma medication use substantially increased the graft failure rate. Factors not strongly associated with graft failure included age, gender, diabetes, smoking, and graft size. The risk of graft failure is significantly increased in eyes with pseudophakic or aphakic corneal edema compared with Fuchs' dystrophy, independent of lens status, and in eyes with a history of glaucoma. Proprietary or commercial disclosure may be found after the references.