We conducted a prospective, randomized trial comparing the endothelial protective effects of Healon (Kabi Pharmacia Ophthalmics, Inc., Monrovia, California) and Viscoat (Alcon Surgical, Inc., Ft. Worth, Texas) in 59 eyes of 59 patients undergoing iris-plane or posterior-chamber phacoemulsification with posterior-chamber lens implantation. We evaluated postoperative central and superior changes in corneal thickness and corneal endothelial cell density, coefficient of variation in cell size, and percentage of hexagons. In the overall series, at one day postoperatively, corneal thickness increased 17% centrally and superiorly in eyes receiving Healon compared to 12% centrally and 11% superiorly in eyes receiving Viscoat (P < .05). Sixteen weeks postoperatively, superior endothelial cell loss was 11.6% in eyes receiving Healon compared to 2.1% in eyes receiving Viscoat (P < .01). In the iris-plane phacoemulsification group, superior cell loss at week 16 was 13.8% in eyes receiving Healon and 0.5% in eyes receiving Viscoat (P < .04). In the posterior-chamber phacoemulsification group, there were no significant differences between the Healon and Viscoat subgroups. Comparing the surgical techniques, in the Healon group, central cell loss at week 16 was 13.8% in the iris-plane phacoemulsification subgroup and 0.6% in the posterior-chamber phacoemulsification subgroup (P < .03), and coefficient of variation in cell size increased 3.7% in the iris-plane subgroup and decreased 6.8% in the posterior-chamber subgroup (P < .04). In the Viscoat group, there were no significant differences between surgical techniques at week 16. Viscoat provided greater corneal endothelial protection than Healon during iris-plane phacoemulsification. In eyes receiving Healon, posterior-chamber phacoemulsification resulted in less corneal endothelial trauma than the iris-plane technique.