To identify factors distinguishing subsequent neuromyelitis optica (NMO) from multiple sclerosis (MS) after first-ever optic neuritis (ON), we compared ophthalmic findings and MRI features of 24 NMO and 55 MS patients who initially presented with ON. The female-to-male ratio was higher, and bilateral ON was more common in NMO patients than in MS patients (p = 0.044 and p = 0.020, respectively). The visual acuity (VA) score was higher in NMO patients (p = 0.034), and a greater proportion of NMO patients had a VA score ≥ 5 (p = 0.003). The frequency of patients without pattern-reversal and flash visual evoked potentials was higher in the NMO group (p = 0.015). Brain MRI abnormalities were more common in the MS group (p = 0.001). The optic chiasm was affected in 25 % of NMO patients and was unaffected in MS patients, although it did not reach statistical significance (p = 0.096). There were no differences with respect to the severity of swelling and enhancement of the optic nerve. In conclusion, severe optic nerve damage at the first ON attack was associated with subsequent development of NMO, whereas presence of brain MRI abnormalities was associated with developing MS.