PURPOSE: The purpose of this study was to evaluate and compare the 5-year efficacy and safety of accelerated transepithelial (A-epi-on) corneal collagen cross-linking (CXL) with standard CXL (epi-off) in children with progressive keratoconus (KC). METHODS: This prospective cohort study included 78 eyes of patients aged 18 years old or younger with progressive KC who underwent CXL at the Oftalmosalud Institute of Eyes, Lima, Peru. A-epi-on CXL was performed in 32 eyes (30' of impregnation/5' of irradiation at 18 mW/cm2) and epi-off CXL was performed in 46 eyes (30'of impregnation/30' minutes of irradiation at 3 mW/cm2). Visual acuity, refraction, and the Scheimpflug imaging parameters were evaluated preoperatively and postoperatively at 1 and 5 years. RESULTS: The best corrected visual acuity improved to 0.06 logarithm of the minimum angle of resolution (SD: 0.19, P = 0.03) and 0.09 logarithm of the minimum angle of resolution (SD: 0.13, P < 0.001) in the A-epi-on and epi-off groups, respectively. The mean flattening in the mean keratometry was 0.09 diopters (D) (SD: 0.68, P = 0.33) and 3.18 D (SD: 5.17, P < 0.001) in the A-epi-on CXL and Epi-off groups at the 5-year follow-up. Significant differences were found in the change at 1 and 5 years between the groups for cylinder reduction, flat and mean K, and pachymetry (all P < 0.05). The KC progression rate was 9.37% (3/32) in the A-epi-on CXL; no progression was found in the epi-off CXL group at the 5-year follow-up. CONCLUSIONS: Both procedures halted the progression of KC at the 5-year follow-up; however, epi-off CXL was safer and more effective when compared with A-epi-on CXL.