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Purpose: 1% topical 5-fluorouracil (5-FU) is a treatment for ocular surface squamous neoplasia (OSSN) due to its effectiveness, low cost, and tolerable side effect profile. To our knowledge there is no reported sight-threatening corneal complication of 1% 5-FU for the treatment of OSSN. Observations: We report a 78 year-old man with bilateral conjunctival intraepithelial neoplasia (CIN) who developed bilateral corneoscleral ulceration and corneal perforation of the left eye after 1% 5-FU topical treatment. Conclusions and Importance: Our case report describes serious potential complications of 1% 5-FU, reviews possible risk factors associated with poor outcomes, and discusses our treatment approach.