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Purpose: To report long-term clinical results of transepithelial cross-linking with iontophoresis (I-CXL) for progressive keratoconus (KC). Methods: Nineteen eyes of 19 patients treated with I-CXL for progressive keratoconus were included in this prospective clinical study. Preoperatively and in all available follow ups (6, 12, 24, 36, 48, 60, 72 and 84 months), the following parameters were measured. Corrected distance visual acuity (CDVA), spherical equivalent and cylinder refraction, corneal topography and aberrometry (Costruzione Strumenti Oftalmici (C.S.O.), Florence, Italy), Scheimpflug tomography (OCULUS Optikgeräte GmbH; Wetzlar, Germany). Definition of progression after I-CXL was 2/3 of the following criteria: increase of “A” value, increase of “B” value, decrease of minimal thickness evaluated with the ABCD progression display above 95% confidence interval for post-CXL population when compared to the scan 12 months post-op. Results: The mean follow-up time of included patients was 63 months (range 12 to 84 months, 5 patients reached 84 months). The general linear model showed no significant change over time in CDVA, Maximum Keratometry, Thinnest point, and A, B, C values of the Belin Progression Display (p > 0.05). Conversely, comatic and high order aberrations decreased significantly over time (both p =< 0.001). Five cases (26.31%) showed significant progression after a mean of 55 months (range 36–72) of follow up. Conclusion: Our study shows the ability of I-CXL to slow down KC progression in the majority of included patients, improving high order and comatic aberrations. A 26% progression rate was reported.