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Fluorouracil (5-fluorouracil, 5-FU) is a pyrimidine analogue that was originally known for its widespread use as an anticancer drug. The ability of 5-FU to reduce fibroblastic proliferation and subsequent scarring has made it an important adjunct in ocular and periorbital surgeries. It is used in primary glaucoma filtering surgeries and in reviving failing filtering blebs, in dacryocystorhinostomy, pterygium surgery, and in vitreoretinal surgery to prevent proliferative vitreoretinopathy. In addition, 5-FU is also gaining recognition in the treatment and surgical management of ocular surface malignancies like ocular surface squamous neoplasia; however, the specific action of the drug on highly proliferating cells limits its use in primary acquired melanosis of the conjunctiva. When applied topically, this drug has a low rate of sight-threatening adverse effects, is inexpensive, and is easy to administer, making it an important tool in enhancing the success rate in ophthalmic surgery and in reducing the recurrence of ocular surface neoplasia.