Background: It is essential to distinguish acute disseminated encephalomyelitis (ADEM) from MS early. Our aim was to determine MRI features at baseline and follow-up to distinguish pediatric ADEM from MS stratified according to age at onset. Methods: Using hospital ICD-10 codes for acquired demyelinating syndromes from a nationwide register and subsequent chart review, we identified 52 children (<18 years) with ADEM and 66 children with MS. We undertook a retrospective analysis of MRI scans at onset and at follow-up. The MRI rater was a senior neuroradiologist blinded to clinical characteristics. Results: At baseline, children with ADEM had more diffuse poorly demarcated lesions, particularly in the basal ganglia/thalamus (p = 0.001) and cerebellar peduncles (p < 0.0001). Further, longitudinal extensive transverse myelitis was strongly associated with ADEM (p<0.0001). Children with ADEM had fewer contrast-enhancing lesions (p = 0.0004), occipital lesions (p = 0.01), optic nerve lesions (p = 0.01), periventricular lesions, well-defined lesions only (p<0.0001), and fewer fulfilled dissemination in time according to the McDonald 2017 criteria (p = 0.005). On baseline MRI, dissemination in space and time was fulfilled in 17% of children with ADEM and in 34% of children with MS (p = 0.06), and 60% of children with ADEM fulfilled the criterion for dissemination in space. The mean time from baseline MRI to follow-up MRI was 1.0 year for children with ADEM and 2.1 years for children with MS. On follow-up MRI, 85% of children with ADEM had partial or complete T2 lesion resolution, but in the 58% without complete resolution lesions were predominantly frontal. Only 47% of children with MS had partial or complete T2 lesion resolution, and therefore more MRI features differed between children with ADEM and MS on follow-up. MRI had the greatest distinguishing value after age 11 years because MS is exceptional in the first decade of life. Conclusion: Age at onset and the timing of MRI in relation to disease onset are critical in the interpretation of MRI to distinguish between ADEM and MS.