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AIM: To analyze microstructural changes, after epithelium-off corneal collagen cross-linking for progressive keratoconus by using <i>in vivo</i> confocal microscopy(IVCM).<p>METHODS: Totally 15 eyes in 15 patients with progressive keratoconus were treated by the photochemical epithelium-off cross-linking method. Patients were examined pre- and postoperatively by confocal <i>in vivo</i> laser scanning microscopy.<p>RESULTS: The sub-basal nerve significantly decreased or disappeared and the anterior corneal stroma had a honeycombed appearance but without the typical hy-perreflective keratocyte nuclei after early stage of treatment. At 3mo postoperatively, the corneal stroma had a small amount of the typical hy-perreflective keratocyte nuclei. After 12mo,the corneal stroma almost recovered to the preoperative level, but the sub-basal nerve were still sparse and didn't reach the preoperative level. The endothelial cells showed no significant reduction during the follow-up.<p>CONCLUSION: This IVCM study revealed loss of the sub-basal nerve plexus and loss of anterior stromal keratocytes in the early postoperative period, with regeneration of keratocyte repopulation by 12mo postoperatively, but the sub-basal nerve plexus didn't reach the preoperative level.