The aim of this study is to compare the long-term effects of transepithelial corneal crosslinking with two continuous cycles of iontophoresis (EI-CXL) and conventional corneal crosslinking (C-CXL) in adults with progressive keratoconus. Methods A retrospective analysis was conducted in adults who underwent C-CXL or EI-CXL between 2013 and 2015. Visual acuity, corneal tomography, anterior segment optical coherence tomography, in vivo corneal confocal microscopy (IVCM), and endothelial cell count (ECC) were performed preoperatively and 5 years postoperatively. Results Sixty-eight patients with a mean age of (24.3 ± 3.8) years were included, 34 for each group. After CXL, UCVA or BCVA remained stable, while the spherical diopter, cylinder diopter, spherical equivalent, and K max significantly decreased at 1, 2, and 3 years in both groups than baseline (P < 0.05). No significant differences were found in any refractive or tomographic parameters as well as the minimal corneal thickness between groups during follow-up. At 5 years, K max was slightly higher in EI-CXL group (58.16 ± 6.28) than that of C-CXL group (57.46 ± 4.98). At 3 and 5 years, the minimal corneal thickness in C-CXL group was still significantly lower than baseline (P < 0.05). IVCM demonstrated the demarcation zone at a mean depth of (302.0 ± 41.7) μm after C-CXL, and at (251.2 ± 28.1) μm after EI-CXL (P < 0.001). Keratocyte repopulation was detectable at all follow-up timepoint in both groups. Postoperative complications including progression were recorded in 6 patients (11.7%) after C-CXL and 3 patients (8.8%) after EI-CXL. ECC remained stable in both groups. Conclusion EI-CXL showed approximate efficacy with C-CXL in stabilizing progressive keratoconus in adults. EI-CXL has the potential to be a preferable transepithelial protocol. Keywords Progressive keratoconus. Iontophoresis. Transepithelial corneal crosslinking. Tomography. In vivo confocal scanning microscopy Key message Most previous data revealed inferior efficacy of transepithelial corneal crosslinking assisted by iontophoresis when compared to conventional corneal crosslinking. The limited riboflavin penetration into the corneal stroma is considered as one of the critical inadequacies of standard transepithelial iontophoresis. In this retrospective five-year analysis, no significant differences of the long-term refractive and visual outcome were found between conventional corneal crosslinking and transepithelial corneal crosslinking assisted by two continuous cycles of iontophoresis. Improved stromal penetration depth was achieved by two continuous cycles of iontophoresis.