AIM: To investigate the incidence, risk factors, clinical course, and outcomes of corneal epithelial defects (CED) following vitreoretinal surgery in a prospective study setting. METHODS: This was a post-hoc analysis of all participants in DISCOVER intraoperative optical coherence tomography study. Subjects with CED 1d after surgery without intraoperative corneal debridement was defined as the postoperative CED group. Subjects who underwent intraoperative debridement were defined as intraoperative debridement group. Eyes were matched 2:1 with controls (eyes without postoperative CED) for comparative assessment. The primary outcomes were the incidence of CED on postoperative day one and the incidence of required intraoperative debridement. Secondary outcomes included time to defect closure, delayed healing (>2wk), visual acuity (VA) and presence of scarring at one year and cornea consult. RESULTS: This study included 856 eyes that underwent vitreoretinal surgery. Intraoperative corneal debridement was performed to 61 (7.1%) subjects and postoperative CED developed spontaneously in 94 (11.0%) subjects. Significant factors associated with postoperative CED included prolonged surgical duration (P=0.003), diabetes mellitus (P=0.04), postoperative ocular hypotension (P<0.001). Prolonged surgical duration was associated with intraoperative debridement. Delayed defect closure time (>2wk) was associated with corneal scar formation at the end of the 1y in all epithelial defect subjects (P<0.001). The overall rate of corneal scarring for all eyes undergoing vitrectomy was 1.8%. CONCLUSION: Prolonged duration of surgery is the strongest factor associated with both intraoperative debridement and spontaneous postoperative CED. Delayed defect closure is associated with a greater risk of corneal scarring at one year. The overall rate of corneal scarring following vitrectomy is low at <2%.