Association between the use of diclofenac sodium (DfNa) eyedrops and the development of a postkeratoplasty persistent epithelial defect (PED) of the cornea were studied. In 100 consecutive patients undergoing penetrating keratoplasty who had no limbal or conjunctival epithelial abnormalities, 12 (12.0%) developed PED (persistence of epithelial defect for > 8 days after keratoplasty) postoperatively. The use of DfNa eyedrops correlated significantly with the development of PED (p = 0.0001, chi-square test). DfNa eyedrops were used in 19 eyes postoperatively, eight of which (42.1%) showed signs of PED. The type of preservation media, preservation time, indications for keratoplasty, or the surgical procedures performed did not correlate with the development of PED. These results indicate that DfNa eyedrops are toxic to the corneal epithelium postkeratoplasty. The eyedrops should be used with great care in patients with disorders of the corneal epithelium.