BACKGROUND:: Patients with neuromyelitis optica (NMO) and multiple sclerosis (MS) both can present with acute optic neuritis (ON), while differing considerably in their prognosis and management. The clinical course, serologic testing results, and brain and spinal cord imaging of these diseases have been well documented. The purpose of this study was to look systematically for any differences in the imaging appearance of the optic nerve in NMO and MS-related ON. METHODS:: Magnetic resonance imaging (MRI) of brain and orbits obtained within 6 weeks of acute ON in patients with securely diagnosed NMO (n = 6) and MS (n = 11) were retrospectively analyzed by a neuroradiologist masked to the clinical diagnosis. Standardized scoring system was used to assess and analyze the extent and nature of optic pathway involvement. RESULTS:: No significant differences were observed in the presence, degree, or the type of signal alteration and contrast enhancement of the affected nerve segments between NMO and MS groups. There was a trend toward more posterior involvement of the optic nerve in the NMO group with chiasmatic enhancement exclusively seen in NMO patients. CONCLUSION:: We found a higher propensity of NMO-related ON to affect more posterior parts of the optic nerve, including chiasm, and have simultaneous bilateral disease. Further study with larger sample sizes is needed.