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Background Isolated optic neuritis (ON) in childhood may remain a single episode or mark the clinical beginning of multiple sclerosis (MS). Higher age and pathological cranial MRI (cMRI) at presentation were previously demonstrated as independent risk factors of conversion to MS. Objective To further evaluate potential MS risk factors, including cerebrospinal fluid findings (CSF), in children with ON as a first demyelinating event. Methods Children with isolated uni- or bilateral ON as a first demyelinating event below age 18 were included in this retrospective multicenter cohort study. The minimal follow-up (FU) for those not converting to MS according to McDonald 2010 was 2 years. Age, sex, laterality of ON, cMRI (no vs ≥1 MS-compatible lesion outside the optic nerves) and intrathecal oligoclonal IgG bands (OCB) were assessed as risk factors using simple and multiple Cox proportional-hazards regressions. Results Of 357 included children 284 had uni- and 73 bilateral isolated ON. Median FU of patients not developing MS was 4.2 years (range 2.0–22.0). Univariate analyses revealed age (HR 1.15, 95% CI 1.10–1.22, p Conclusion Cerebrospinal fluid analysis may supplement cMRI to determine the risk of MS in children with isolated ON as a first demyelinating event.