Anatomic features unique to periocular tissues alter the clinical appearance of angioedema, making it difficult to distinguish from cellulitis and other inflammatory conditions. Two patients had prominent periocular manifestations of chronic angioedema with necrotizing vasculitis, a systemic disease often associated with multiorgan involvement. The diagnosis was established by exclusion of other inflammatory disorders and confirmed by biopsy. The scarcity of reports in the ophthalmic literature on chronic angioedema of the eyelids may be caused by its underrecognition. The distinction between chronic angioedema and typical angioedema or urticaria is important because of differences in their diagnostic evaluation, treatment, and prognosis.