Primary graft failure is a rare but major complication of penetrating keratoplasty. An apparent clustering of four cases during a 1-month period led to a review of all 778 keratoplasties performed by nine surgeons at Massachusetts Eye and Ear Infirmary from July 1, 1986 to June 30, 1988. The objectives of this study were (a) to investigate the possibility that cases of primary graft failure occurred in clusters within their physical environment of space, time, and personnel and (b) to determine the frequency of and evaluate possible risk factors for primary graft failure. Twenty-one cases of primary graft failure were found, resulting in an incidence rate of 2.7% during this period. A 13.3% incidence of primary graft failure was found in donor mates, suggesting improper tissue preparation. The charts and eye bank records of the 21 cases and 84 age-matched controls, randomly selected from the group of all keratoplasties, were reviewed for donor-, recipient-, surgeon-, and surgery-related characteristics. Improper tissue preparation was not associated with primary graft failure. An individual surgeon was the most significant risk factor [odds ratio = 6 (95% CI: 2.1-17.0)].