Squamous cell carcinoma arising from conjunctiva in the anophthalmic socket decades following enucleation is rare, but has been previously described. The authors report the first case associated with human papillomavirus (serotype 16) with regional metastases. The patient ultimately underwent orbital exenteration along with parotidectomy and neck dissection which revealed positive lymph nodes. The literature is reviewed relating to this uncommon entity and its management with an analysis of potential contributing risk factors.