We present a case of an 82-year-old man with new-onset neuromyelitis optica (NMO) spectrum disorder, the treatment of which was complicated by a severe pre-existing prednisone allergy. His age caused much initial doubt about his diagnosis, and his corticosteroid allergy altered our management as we attempted to minimize risk to the patient. Our patient was a healthy 82-year-old, right-handed man who presented with sensory loss of the bilateral lower extremities and progressive, painless vision loss. MRI showed bilateral pre-chiasmatic optic nerve and optic chiasm enhancement, along with enhancement within the thoracic spinal cord from T3 to T7. Serum NMO-IgG was positive with a titer >1: 100,000. Due to concern of allergic reaction, our patient initially refused high-dose Solu-Medrol and opted to try plasma exchange alone, but due to worsening of his symptoms we attempted to use dexamethasone as it had a theoretically lower risk of adverse reaction with a known prednisone allergy. There are several cases of elderly-onset NMO in the literature but this is the only case we could find of NMO accompanied by a rare severe allergy to prednisone. This case demonstrates the relative safety of dexamethasone as an alternative to methylprednisolone for acute management of NMO spectrum disorder, though efficacy has not been established in major trials. Cross-reactivity between various systemic corticosteroids is not as well established as topical corticosteroids, so it is difficult to assess the probability of a reaction between prednisone and methylprednisolone.