BACKGROUND: MRI findings influence the risk of patients with optic neuritis (ON) developing clinically definite (CD) multiple sclerosis (MS) but their influence on future disability is less clear. OBJECTIVE: To investigate in patients with ON the influence of lesion number, location and activity, and non-lesion MRI measures obtained on early scans on disability. METHODS: A total of 106 of 143 prospectively recruited patients with ON had reached a scheduled 5-year follow-up, of whom 100 were evaluated clinically. Lesion number, location, and activity measures were analyzed at baseline (within 3 months of onset) and lesion activity measures were studied at 3-month follow-up. Brain atrophy, magnetization transfer ratio, and spectroscopy measures were also analyzed. Ordinal logistic regression assessed the association between early MRI findings and subsequent disability. RESULTS: At median 6 years follow-up, 48% had converted to CDMS and 52% remained with clinically isolated syndrome (median Expanded Disability Status Scale 2 and 1). In the final models, both the presence and the number of spinal cord lesions at baseline (odds ratios [OR] 3.30, 1.94) and new T2 lesions at follow-up (OR 7.12, 2.06) were significant independent predictors of higher disability. Disability was also predicted by the presence at baseline of gadolinium-enhancing lesions (OR 2.78) and number of infratentorial lesions (OR 1.82). Only spinal cord lesions predicted disability in patients converting to CDMS. CONCLUSION: Spinal cord, infratentorial, and gadolinium lesions within 3 months of optic neuritis onset and new T2 lesions after 3 months predicted disability after 6 years; only spinal cord lesions were predictive of disability in those developing clinically definite multiple sclerosis.