Background: Our aim was to propose criteria to distinguish multiple sclerosis (MS) from acute disseminated encephalomyelitis (ADEM) at onset based on age at onset, sex, cerebrospinl fluid (CSF)-specific oligoclonal bands, and MRI. Methods: A neuroradiologist undertook retrospective evaluation of the baseline magnetic resonance imaging (MRI) in a nationwide cohort of children with medical record-validated MS (n = 67) and monophasic ADEM (n = 46). Children with ADEM had at least 5 years of follow-up for relapse. We used forward stepwise conditional logistic regression to develop our criteria based on age at onset, sex, CSF-specific oligoclonal bands, and MRI. We undertook sensitivity analyses using children with ADEM including encephalopathy and polyfocal neurological deficits and in those with onset between 11 and 17 years of age. We estimated accuracy statistics from our criteria and all previously proposed MRI criteria to distinguish MS and ADEM. Results: The best performing criteria to differentiate MS from ADEM were scoring at least three points in the following categories: presence of CSF-specific oligoclonal bands (2 points), occipital lesion (1 point), age 11–17 years (1 point), female sex (1 point). These criteria gave highly reliable discrimination with sensitivity of 95% (95% CI=89%–100%), specificity of 100% (95% CI=100%–100%), and area under the curve of 98% (95% CI=95%–100%). The best performing MRI criteria had area under the curve of 84% (95% CI=78%–91%). Previously proposed MRI criteria had the following areas under the curve: Callen (75%), KIDMUS (82%), and McDonald 2017 criteria (68%). Conclusion: Combining sex, age at onset, CSF-specific oligoclonal bands, and MRI gives highly reliable differentiation between pediatric MS and monophasic ADEM at onset.