In order to evaluate the effect of a commonly used sodium hyaluronate preparation (Healon, Pharmacia AB, Uppsala, Sweden) on the incidence of endothelial rejection, endothelial cell loss, intraocular pressure, and corneal thickness after penetrating keratoplasty, we conducted a randomized clinical trial. Patients were allocated to receive Healon (n = 41) or BSS (Alcon Laboratories, Inc., Fort Worth, TX, U.S.A.; n = 37) during surgery. At 1 year after surgery, the Kaplan-Meier estimate of the proportion remaining free of endothelial rejection was 78.1% (SE 6.5%) in the Healon group, and 70.6% (SE 7.9%) in the BSS group. Survival analysis showed no overall difference in endothelial rejection between groups. The percent loss in endothelial cell density showed substantial variability within each group, but for those followed 2 years after surgery, the amount of loss was significantly less in Healon-treated patients (17.3% versus 30.2%). Four Healon patients required medication for intraocular pressure rises in the early postoperative period, and the average intraocular pressure 1 day after surgery was greater in the Healon group (18.2 versus 13.7 mm Hg). Corneal thickness was slightly greater in patients receiving Healon, but no clinically important differences were noted.