PURPOSE: To evaluate the biomechanical changes and ad-vanced oxidation protein products (AOPP) production after different corneal cross-linking (CXL) protocols with or with-out oxygen supplementation.METHODS: Ovine eyes in the study were equally distributed to five groups as control, standard Dresden protocol, diluted alco- hol-and iontophoresis-assisted CXL (DAI-CXL), and 0.1% and 0.2% riboflavin-mediated iontophoresis-assisted CXL with oxy-gen supplementation (I-CXL). Corneas that received CXL were divided into two equal parts, one part was used for uniaxial tensiometry and one part was used for AOPP measurement.RESULTS: All treatment groups showed higher Young's modu-lus and stiffness compared to the control group (P < .05). Both oxygen-assisted I-CXL groups with 0.1% and 0.2% riboflavin con-centrations had higher corneal Young's modulus (P = .009 and .006, respectively) and stiffness (P = .009) values, whereas the DAI-CXL group had lesser Young's modulus and stiffness values (P = .032) compared to the Dresden protocol group. All treatment groups showed higher AOPP concentrations compared to the control group (P < .05). DAI-CXL and I-CXL groups showed similar AOPP formation compared to the Dresden protocol (P = .673).CONCLUSIONS: When the epithelium is intact, the desired in-crease in corneal stiffness might not be achieved. However, increasing the oxygen in the environment might provide a suf-ficient increase in stiffness in cases undergoing epithelium-on I-CXL, which might be promising in terms of shortening the CXL therapy and decreasing the complications.