Objective: Ocular surface squamous neoplasia (OSSN) is the most common type of non-melanocytic ocular surface tumor. Conjunctival intraepithelial neoplasia (CIN) is a type of OSSN that be medically managed by either topical interferon alpha-2b (IFN α-2b), 5-fluorouracil (5-FU), or mitomycin C. While a paradoxical response to IFN α-2b in the HIV population has been reported, we report a case of a paradoxical response in an immunocompetent individual. Methods: A 65-year-old immunocompetent female presents to the clinic with CIN. Results: She is started on topical IFN α-2b, resulting in an unexpected hypopyon, increased corneal epithelial defect, and increased size of the lesion. Switching to topical 5-FU resulted in decreasing size of the CIN lesion and resolution of the epithelial defect. Conclusions: Topical IFN α-2b can produce a paradoxical worsening of CIN lesions in some patients. Providers should be aware of this reaction, as well as the presenting signs and symptoms, to make appropriate treatment changes when treating CIN.