The diagnosis of acquired demyelinating syndromes of the central nervous system in children requires exclusion of other acute central nervous system disorders. In a 23-site national demyelinating disease study, standardized clinical, laboratory, and magnetic resonance imaging (MRI) data were obtained prospectively from onset, and serially at 3, 6, and 12 months and annually. Twenty of 332 (6%) participants (mean [SD] age, 10.21 [4.32] years; 12 (60%) female) were ultimately diagnosed with vascular disorders (primary or secondary central nervous system vasculitis, vasculopathy, stroke, or migraine, n = 11 children), central nervous system malignancy (n = 3), mitochondrial disease (n = 2), or central nervous system symptoms in the accompaniment of confirmed infection (n = 4). Red flags that may serve to distinguish disorders in the differential of acquired demyelination are described.