Optic Neuritis (ON) might unfold either as a single intracranial neuritis or as multiple sclerosis, a widespread demyelinating disorder. Different herpes viruses have been proposed as potential participants in the etiology of multiple sclerosis (MS). To analyze the potential presence of herpes viruses in blood and subarachnoid area at the time of ON and contrast the findings according to long-term evolution either as intracranial neuritis or as progression to multiple sclerosis.In a prospective investigation we searched the presence of DNA from 5 herpes viruses (HSV-1, HSV-2, VZV, EBV and HHV6) in CSF and blood lymphocytes from 54 patients with ON, patients were followed 62 ± 3 months; those who developed MS were separated from those with ephemeral ON. Long-term prognosis of ON was related to DNA findings.As compared with controls, DNA from HSV-1 was significantly more frequent in CSF and blood from cases with ON; VZV and HSV-2 were found only in CSF; EBV was found only in blood samples (p < 0.006).Our results point out the potential participation of HSV, VZV and EBV in ON; suggesting the intervention of various herpes viruses as triggering agents of autoimmunity. However, the number of positive cases was minor than negative cases. Also, our results suggest that the etiological mechanisms in ON could be similar to those of neuritis of the facial nerve (Bell's palsy).