Purpose: To evaluate epithelial signs and pain after epithelial-on corneal collagen cross-linking (Epi-on CCL) with new transepithelial riboflavin formulation and epithelial-off corneal collagen cross-linking (Epi-off CCL) with standard riboflavin formulation and to compare pain and duration of epithelial healing between both techniques. Methods: Thirty-nine eyes of 39 patients undergoing Epi-on CCL and 39 eyes of 39 patients undergoing Epi-off CCL were evaluated. Corneal epithelial signs and durations of corneal epithelial healing and subjective pain scores after the procedures were recorded and compared between 2 groups. Results: Total epithelialization was observed after 2.70.7 days in Epi-on CCL and 2.3 +/- 0.4 days in Epi-off CCL (P=0.006). The mean pain score on the first day was 3.1 +/- 0.6 in Epi-on CCL and 2.3 +/- 0.4 in Epi-off CCL with a significant difference (P=0.0001). Conclusion: The epithelial damage was observed in both procedures; also, the epithelial healing time was longer in Epi-on CCL and it is of great importance that the patients should have therapeutic contact lenses until the epithelium heals in both procedures. The Epi-off CCL group had less pain scores than the Epi-on CCL group and more pain problems after Epi-on CCL still remains. The patient should be informed about pain, even if the Epi-on CCL procedure was performed.