Purpose To investigate the impact of oxygen delivery on the clinical outcomes of accelerated transepithelial corneal cross-linking (A-TE CXL). Methods Fifty-seven eyes of 44 progressive keratoconus (KCN) patients were randomly separated into two age-sex-matched groups. Twenty-nine eyes of 23 KCN patients that underwent oxygen-supplemented A-TE CXL formed the study group and 28 eyes of 21 patients treated with the same procedure but under room air conditions formed the control group. All patients were examined preoperatively, one, six and twelve months after the procedure. The logMAR spectacle-corrected distance visual acuity (CDVA), maximum keratometry (Kmax), mean keratometry, apical posterior keratometry, cylindrical power, minimum central corneal thickness, keratoconus vertex front and back, ocular aberrations, endothelial cell density (ECD), demarcation line depth (DLD) and proportion measures were recorded for statistical analysis. Results The preoperative, 1st, 6th and 12th months mean Kmax values of the study group were 55.14 +/- 3.99D, 54.85 +/- 3.82D, 54.37 +/- 3.84D and 54.40 +/- 3.86, respectively, and 54.47 +/- 3.17D, 54.52 +/- 2.97D, 54.25 +/- 2.95D and 54.20 +/- 2.97 in the control group. The mean Kmax value was decreased significantly more in the oxygen-supplemented group after 12 months compared to the control group (p = 0.019). The mean DLD was also significantly deeper in the study group (320 +/- 17 mu m) compared to the control group (269 +/- 19 mu m). There was no significant difference between the two groups in terms of ECD alterations at any of the time intervals (p > 0.05). Conclusion Keratoconus progression was significantly halted in both groups 12 months after the treatment. In addition, oxygen supplementation during A-TE CXL further significantly increased clinical outcomes compared to room air conditions without any significant change in ECD measures.