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To evaluate the effect of a regenerative agent (RGTA) [Cacicol20—poly(carboxymethyl glucose sulfate); OTR3, Paris, France] on corneal reepithelialization and pain after corneal cross-linking (CXL) for keratoconus.In this prospective comparative (contralateral) clinical study, patients with bilateral progressive keratoconus underwent CXL treatment. The corneal epithelium during CXL was removed using transepithelial phototherapeutic keratectomy (Cretan protocol). One eye of each patient was randomly instilled with an RGTA (Cacicol20) once a day (study group), whereas the fellow eye was instilled with artificial tears (control group). Patients were examined daily until complete reepithelialization. Postoperative examinations included slit-lamp biomicroscopy to assess the epithelial defect size and subjective evaluation of pain.The study enrolled 18 patients (36 eyes). The mean epithelial defect size for study and control groups was 19.6 ± 4.2 mm2 versus 21.5 ± 2.8 mm2, respectively, at day 1 (P = 0.019) and 6.4 ± 3.4 mm2 versus 7.9 ± 4.3 mm2, respectively, at day 2 (P = 0.014). At day 3 postoperatively, 61.1% of study eyes were fully reepithelialized, compared with 11.1% of control eyes (P = 0.002).RGTA (Cacicol20) instillation seems to result in faster corneal reepithelialization after CXL in this study. However, there was no significant effect in subjective pain/discomfort.