Unilateral eye swelling, redness, and pain may represent a diagnostic challenge to many clinicians. The differential diagnosis is broad and includes both nonemergent and emergent diagnoses. While the emergent diagnoses must be made and treatment initiated immediately, the nonemergent differential also includes life- and vision-threatening entities. The diagnosis of idiopathic orbital inflammatory syndrome (IOIS) is characterized by acute-onset, typically unilateral periorbital swelling, chemosis, and proptosis. It can be differentiated from other entities by radiologic findings and rapid response to corticosteroids; however, it is often a diagnosis of exclusion. We report a case-based discussion including distinguishing features, diagnostic modalities, and treatment of similar entities involving periorbital/orbital edema and conjunctival injection complicated by a past medical history of breast cancer.