To report a case of corneal epithelial plaque formation associated with recombinant human nerve growth factor (cenegermin 0.002%; Oxervate, Dompe[Combining Acute Accent] US Inc., Boston, MA), an as-yet unreported adverse event. A case report and review of literature. A 45-year-old woman presented with a nonhealing 3.25- × 4.25-mm corneal epithelial defect secondary to multifactorial neurotrophic keratitis in the right eye. The epithelial defect was resistant to maximal medical therapy, and so cenegermin 0.002% was initiated, resulting in resolution of the corneal epithelial defect. After 6.5 weeks of treatment, she developed an unusual corneal epithelial plaque, decreased visual acuity, and eye pain. Cenegermin was ceased, after which the lesion resolved, visual acuity improved, and eye pain resolved. Cenegermin 0.002% has emerged as a promising treatment for neurotrophic keratitis. Reported adverse events with this agent have been minor and typically not vision threatening. Here, we describe corneal epithelial plaque formation as a visually significant adverse event that resolved with cessation of cenegermin 0.002%. Although the underlying mechanism is unknown, clinicians should be alerted to the possibility of epithelial plaque formation in patients being treated with recombinant human nerve growth factor for neurotrophic keratitis.