The Optic Neuritis Study GroupArticle studied 389 patients with acute optic neuritis who were enrolled between 1988 and 1991 and followed prospectively for 15 years, with final examination in 2006. The cumulative probability of developing multiple sclerosis (MS) by 15 years was 50% (95% confidence interval, 44-56) and was strongly related to the presence of lesions on a non–contrast-enhanced baseline brain magnetic resonance image (MRI). Twenty-five percent of patients with no baseline brain MRI lesions developed MS during follow-up, compared with 72% of patients with 1 or more lesions. After 10 years, the risk of developing MS was very low for patients without baseline lesions but remained substantial for those with lesions. The presence of brain MRI abnormalities at the time of an optic neuritis attack is a strong predictor of the 15-year risk of developing MS. In the absence of MRI lesions, male sex, optic disc swelling, and atypical clinical features of optic neuritis are associated with a low likelihood of developing MS. This natural history information is important when considering prophylactic treatment for MS at the time of a patient's first acute optic neuritis attack.