Three patients had residual or recurrent tumour following excision of large ocular surface squamous neoplasia (OSSN) lesions, which did not resolve despite the use of adjunctive cryotherapy and topical mitomycin-C therapy. The residual tumour was treated with topical or subconjunctival injectable interferon α 2b. All three eyes had complete resolution of the OSSN lesions after an average of 6 weeks (range 4–8 weeks) of treatment with interferon α 2b. No regrowth was seen during the follow-up period of 22.7 ± 32.3 months (range 5–60 months). No adverse reactions or complaints were reported during and following interferon use, and previous symptoms from mitomycin-C treatment resolved completely. In these patients subconjunctival or topical interferon was an effective and safe treatment for residual OSSN. Longer follow up is required to confirm the long-term efficacy in prevention of recurrences.