PURPOSE: To compare efficiency and safety of epithelium-off corneal cross- linking (CXL) and transepithelial cross- linking (TE-CXL) in keratoconus patients. METHODS: Uncorrected and corrected visual acuity, simulated keratometry, corneal topography and pachymetry (Sirius, CSO Italy) data were evaluated at baseline and at 3, 6, and 12 months in 15 keratoconus patients were treated with TE-CXL and 20 keratoconus patients were treated with conventional or epithelium-off CXL. All patients had corneal thickness of 400 μm thinnest corneal thickness or more. RESULTS: In the epithelium-off CXL group (20 patients, 25 eyes; mean age, 17.7 ± 2.9 years), a significant improve- ment at month 12 was present for Kmax [-1.29 diopters (D), P = 0.01], Kmin (-3.2 D, P = 0.001), mean K (-1.47 D, P = 0.01), surface asymmetry index (-0.86 D, P = 0.001), inferior-superior symmetry index or symmetry index front SIF (-0.56 D, P = 0.01), and anterior elevation at the thinnest location (-2.82 D, P = 0.01) and at the apex (-2.27 D, P = 0.01). Postoperative corneal edema lasted 2 weeks in 16 eyes (64%) and more than one month in 2 eyes (8 %). In the TE-CXL group (15 patients, 18 eyes; mean age, 15 ± 4.2 years), a significant improvement at month 12 was present for Kmax (-1.01 D, P = 0.02), Kmin (-2.04 D, P = 0.01), mean K (-1.25 D, P = 0.01), surface asymmetry index (-0.64 D, P = 0.001), inferior-superior symmetry index or symmetry index front SIF (-0.55 D, P = 0.001), and anterior elevation at the thinnest location (-2.96 D, P = 0.01) and at the apex (-2.19 D, P = 0.01). Mild postoperative corneal edema after TE-CXL was observed and lasted for few days. TE-CXE was significantly less painful than epithelium-off CXL but the latter had more effective results. CONCLUSION: TE-CXL was less painful with fewer complications but less effective than epithelium-off CXL at 12 months follow up. In short, conventional epithelium-off CXL is better than transepithelial CXL regarding efficacy and visual improvement.