Objective The aim of the study was to assess the safety and efficacy of epithelium-off corneal cross-linking versus epithelium-on cross-linking in the treatment of keratoconus. Patients and methods This study was performed on 42 eyes of 22 patients who were divided into two groups. The first group was the epithelium-off cross-linking (CXL) group that included 23 eyes of 12 patients, whereas the second group was the epithelium-on cross-linking group (the TECXL group) that included 19 eyes of 10 patients. Results On comparing the effect of epi-off and epi-on we found that epithelium-on CXL is superior to epithelium-off CXL regarding pain, complications, early patient convalescence as we found significant difference between epi-on and epi-off groups in postoperative complications. In epithelium-on CXL regarding eight (42%) eyes had pain, 0 eye had delayed reepithelization, one (5.26%) eye had stromal haze, and six (31.57%) eyes had treatment failure. However, epithelium-off CXL is superior to epithelium-on CXL regarding the efficacy in visual stabilization and improvement as we found a significant improvement in anterior elevation and Kmax with P = 0.04 and 0.02, respectively. Epithelium-off CXL had significant reduction in Kmax with P = 0.03, anterior elevation had significant reduction with P = 0.04 epithelium-on CXL having nonsignificant change in Kmax and anterior elevation. Conclusion Actually, in this study, it was found that TECXL was the procedure of choice for patient comfortability, safety, and convalescence. However, the results of the study confirmed that epithelium-off CXL was the procedure of choice for the patient benefit and guaranteed visual stabilization and additional visual improvement convalescence.