To investigate the effect of high-fluence corneal collagen cross-linking (CXL) with riboflavin and ultraviolet-A in the management of progressive keratoconus. Preliminary results from a prospective cohort study. Seven eyes from 7 patients with progressive keratoconus subjected to CXL were included. CXL was performed as a standard epithelium-off procedure, irradiating with high-fluence settings (18 mW/cm(2) for 5 minutes). Endothelial cell density (ECD), speed of postoperative epithelial healing, maximal and average keratometric readings (Kmax and Kmean, respectively) of the anterior corneal surface, and corrected distance visual acuity (CDVA) were evaluated preoperatively and at 1 and 6 months after CXL. One-way analysis of variance was applied for statistical analysis. P values less than .05 were considered significant. ECD did not change significantly postoperatively and complete epithelial healing occurred in all eyes within 96 hours postoperatively. No morphological alterations in the corneal limbus were observed. Kmax, Kmean, and CDVA showed no significant changes at 1 and 6 months postoperatively. No complications were observed postoperatively. Although the preliminary results are not sufficient for a valid evaluation of the biomechanical effect and the overall safety profile of high-fluence CXL in vivo, they demonstrate that CXL at 18 mW/cm(2) for 5 minutes affects neither endothelial cell density nor the speed of epithelial healing, an indirect indicator of limbal stem cell function.