A 64-year-old healthy female presented with a papillomatous limbal lesion involving 6 clock hours of superior limbus and diffuse involvement of upper tarsal conjunctiva of left eye of 6 months duration. Excision of superior limbal lesion on histopathology showed carcinoma in situ with focal breach in basement membrane and moderate degree of differentiation. The surgical base and margins were uninvolved. The tarsal lesion was initially treated with subconjunctival interferon alpha 2b (IFN alpha 2b) (3 cycles of IFN alpha 2b) with poor response. Subsequently treatment with topical mitomycin C 0.04% showed a dramatic response in the upper eyelid tarsal lesion. A small residual lesion needed excision. One year after treatment, she was completely tumor-free. In multifocal ocular surface squamous neoplasia, multimodal treatment with excision and topical mitomycin C may be effective in cases refractory to immunotherapy.