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Purpose: To evaluate the clinical characteristics of pediatric patients with progression of keratoconus after accelerated iontophoresis-assisted epithelium-on corneal cross-linking (I-ON CXL) and to assess the efficacy and safety of re-treatment using accelerated epithelium-off CXL (epi-OFF CXL). Methods: Sixteen eyes of 16 patients (mean age: 14.6 ± 2.5 years) with keratoconus underwent I-ON CXL. The main outcome measures were uncorrected distance visual acuity, corrected distance visual acuity, maximum keratometry index (Kmax), minimum corneal thickness, elevation front and elevation back measured at the thinnest point, total higher order aberrations root main square (HOA RMS), coma RMS, and spherical aberration. An increment of Kmax greater than 1.00 diopter (D) and a decrease of greater than 20 µm in pachymetry were considered to determine the progression of keratoconus. Patients with progression of keratoconus after I-ON CXL were re-treated using an epi-OFF CXL protocol. Results: Two years after I-ON CXL, 12 patients showed progression of keratoconus, whereas 4 patients were stable. There was significant worsening of Kmax ( P = .04) and steepest keratometric reading ( P = .01). Furthermore, a significant correlation was documented between progression of keratoconus and age ( P = .02). These patients were re-treated using an epi-OFF protocol and after 2 years all patients were stable, and a statistically significant reduction of the mean Kmax ( P = .007), HOA RMS ( P = .05), and coma RMS ( P = 05) was observed. Conclusions: I-ON CXL was ineffective in the treatment of pediatric keratoconus in younger children, whereas it had an efficacy of 2 years in older children. Re-treatment using epi-OFF CXL proved effective to halt progression of keratoconus after I-ON CXL failure. [ J Pediatr Ophthalmol Strabismus . 20XX;X(X):XX–XX.]