The prevalence of cranial nerve involvement in Multiple Sclerosis (MS) varies across studies. It has been speculated that first presentation of disease with cranial nerve involvement - except for optic neuritis - may be associated with milder progression. This study compares the clinical outcome of patients with MS in a 4-year follow-up of patients with initial symptoms of optic neuritis (ON) versus those with other cranial nerve (OCN) involvement. Retrospective analysis of MS patient database of a tertiary referral university MS center. We included treatment-naïve patients diagnosed with MS according to the revised McDonald criteria, who presented with their first clinical symptoms suggestive of ON or OCN. Patients were required to have regular clinical and radiological follow-up visits (at least two outpatient visits per year and one annual 1.5T MRI), and no comorbidities. The number of relapses and the Expanded Disability Status Scale (EDSS) scores were assessed at six-month intervals during clinic visits. The primary outcome was the number of relapses observed during the study period, comparing the ON and OCN groups. Several statistical analyses were performed, including multiple linear regression, Cox proportional hazards model, one-way ANOVA, and odds ratios, to compare the groups. Of the 84 patients included, none had comorbities (e.g., overlap with other inflammatory diseases, neoplasm etc.). Fifty-five presented with ON and 29 with OCN (e.g., diplopia, trigeminal pain, hearing or vestibular symptoms) at onset. Patients with ON were younger than those with OCN symptoms (p = 0.02), had a higher risk of relapse (more than two relapses) (OR: 1.53) and greater disability (incremental EDSS) over the 4-year follow-up (OR: 1.60). Patients with OCN involvement at the onset experienced fewer relapses and had better EDSS scores at the 4-year follow-up compared to those with ON at onset. These preliminary findings suggest that MS onset with OCN involvement may be associated with a more favorable disease course.