Background: Recent studies demonstrate early diffuse central nervous system (CNS) inflammation in patients with multiple sclerosis (MS). The clinically unaffected (fellow) eye of patients with unilateral optic neuritis (ON) may reflect the status of normal-appearing white matter in the CNS, which can be assessed electrophysiologically. Objective: To study the relationship between electrophysiological parameters in the fellow eye of ON patients, and risk of conversion to MS. Methods: Forty-eight consecutive patients with acute unilateral ON were examined 12 months after ON of which 14 had MS, 19 remained high risk (HR) for MS, and 15 had low risk (LR) for MS according to McDonald's criteria. Twenty-five age-matched controls were also tested. Amplitude and latency of multifocal visual evoked potential (mfVEP) in the fellow eyes of patients at 12 months were analyzed and compared with controls. Results: Average mfVEP amplitude was 240 ± 35, 232 ± 36, 181 ± 38, and 169 ± 48 nV for controls, LR, HR, and MS groups respectively. Average mfVEP latency for controls, LR, HR, and MS patients was 139.7 ± 5.5, 141.7 ± 3.6, 145.9 ± 8.9, and 152.0 ± 9.9 ms respectively. Conclusions: The magnitude of latency prolongation and amplitude decline 12 months after the initial episode was proportional to the risk of MS. The prognostic significance of these changes as predictors of subsequent MS should be investigated longitudinally.