We investigated the paraclinical profile of monosymptomatic optic neuritis (ON) and its prognosis for multiple sclerosis (MS). The correct identification of patients with very early MS carrying a high risk for conversion to clinically definite MS is important when new treatments are emerging that hopefully will prevent or at least delay future MS. We conducted a prospective single observer and population-based study of 147 consecutive patients (118 women, 80%) with acute monosymptomatic ON referred from a catchment area of 1.6 million inhabitants between January 1, 1990 and December 31, 1995. Of 116 patients examined with brain MRI, 64 (55%) had three or more high signal lesions, 11 (9%) had one to two high signal lesions, and 41 (35%) had a normal brain MRI. Among 143 patients examined, oligoclonal IgG (OB) bands in CSF only were demonstrated in 103 patients (72%). Of 146 patients analyzed, 68 (47%) carried the DR15,DQ6,Dw2 haplotype. During the study period, 53 patients (36%) developed clinically definite MS. The presence of three or more MS-like MRI lesions as well as the presence of OB were strongly associated with the development of MS (p < 0.001). Also, Dw2 phenotype was related to the development of MS (p = 0.046). MRI and CSF studies in patients with ON give clinically important information regarding the risk for future MS.