OBJECTIVE To evaluate the relationship between topical corticosteroids and other variables and the risk for rejection after penetrating keratoplasty for keratoconus. METHODS The records of all keratoconus patients who, after their first penetrating keratoplasty in that eye, experienced a first episode of corneal graft rejection during a specific 3-year period were retrospectively reviewed in a case-control fashion. Twenty-three cases were identified, and they were matched with 3 controls each, for a total of 69 controls and 92 total patients. Multiple variables including steroid potency, recent steroid tapering, and length of time on the current level of steroids were analyzed to see whether there were any significant relationships between postoperative changes in steroid management and rejection. In addition, other variables such as graft size, suture technique, recent suture removal, suture status at the time of the rejection episode, and prior grafting in the fellow eye were examined to determine if any of these factors were associated with a higher risk of graft rejection. RESULTS Most of the proposed risk factors, including steroid dose and tapering, differing suturing techniques, loose and/or broken sutures at the time of rejection, percentage of sutures remaining at the time of rejection, and prior grafting in the fellow eye, did not correlate with the risk of rejection. Only graft size had a correlation, with host trephination size > or = 8.25 mm having a nearly sixfold increased risk of rejection (P = 0.015). Most patients (70%) were diagnosed with rejection at a scheduled office visit rather than at an emergency visit, and correspondingly, nearly one half (43%) had no symptoms when rejection was identified. There was no significant difference in final best-corrected visual acuities between the cases and controls, and 91% of the corneas that underwent rejection did not progress to graft failure, remaining centrally clear at most recent follow-up. CONCLUSIONS In this study, the most important risk factor for rejection after corneal transplantation for keratoconus was the size of the graft. Physician detection of rejection is paramount, because a graft rejection episode is more often diagnosed at a scheduled office visit than at an emergency visit. Fortunately, progression to graft failure can usually be prevented if treatment is started promptly and intensively.