BACKGROUND Penetrating keratoplasty is one of the most common and successful ophthalmic procedures. However, controversy and uncertainty still call to question the significance of certain risk factors for graft failure. METHODS A consecutive series of 1819 penetrating keratoplasties at a single center was studied to determine donor and recipient risk factors for graft failure. Mean follow up was 2.3 years (range, 1 to 96 months) with 139 (7.7%) eyes lost to follow up. RESULTS Previous graft failure was the most significant risk factor for secondary failure (P = .0013). The risk of failure significantly decreased with increased postoperative time. Significant patient risk factors for secondary failures in initial grafts included race (P = .01), age (P = .004), iris color (P = .02), use of preoperative glaucoma medications (P = .0008), deep stromal vascularization (P = .002), and host horizontal diameter (P = 0.007). Significant risk factors for failures associated with immunologic allograft reactions in initial grafts included horizontal corneal diameter (P = .002), donor size (P = .05), differences between horizontal corneal diameter, and both donor size (P = .02) and recipient trephination size (P = .01). However, deep stromal vascularization was only marginally significant (P = .09). A history of preoperative glaucoma medication usage was not a significant risk factor. CONCLUSIONS The relationship of the recipient's horizontal corneal diameter to immunologic graft rejection is a new risk factor that surgeons can directly control and thereby help avoid graft failure.