Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder characterized by monophasic or recurrent attacks of optic neuritis (ON) and transverse myelitis. NMO spectrum disorders include patients who are seropositive for NMO-IgG antibody and have experienced at least 1 demyelinating attack. NMO has been associated with other autoimmune conditions. We describe a patient diagnosed with autoimmune hemolytic anemia and marginal zone lymphoma, who later developed NMO-IgG seropositive ON. The coexistence of multiple immunologic abnormalities in this patient points to a generalized dysfunction of the humoral immune system. History of autoimmunity should alert the clinician to the possibility of NMO spectrum disorder in a patient presenting with isolated ON.