BACKGROUND: Most patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD) require life-long immunosuppression to prevent relapses. Patients who are untreated or undergo de-escalation of therapy typically experience severe disabling relapses. We present a series of patients who, despite not receiving immunosuppression, developed minimal disability. METHODS: Case series from a UK national NMOSD referral centre. We defined benign disease as an estimated disability status scale score of ≤ 3 after a minimum of 4 years without immunotherapy. RESULTS: Of 153 AQP4-IgG NMOSD patients, 8 (5.2%) had a benign disease course after a median follow-up of 7.5 years (Q1: 5.8, Q3: 13.3) without immunotherapy. All patients were female, and 7/8 were of White racial background. Clinical attacks included isolated optic neuritis, transverse myelitis, area postrema syndrome or combinations of these syndromes. CONCLUSION: The presence of benign NMOSD and the potential for safe de-escalation of therapy in NMOSD remains unclear. This study suggests that both may be possible. Further studies of similar cases could provide valuable insights and identify biomarkers for safe treatment discontinuation.