A 21-year-old female with relapsed acute myelogenous leukemia (AML) without CNS involvement underwent a second allo-HST. Ten weeks post-transplant, the patient was admitted for EBV-PTLD, treated with rituximab. MR brain obtained for complaint of headache demonstrated two punctate areas of T2 hyperintensity without enhancement, suggestive of subacute infarcts. Six days later, patient developed behavioral changes. Repeat MR brain showed new and increased foci of white matter T2 hyperintensities, now with dominant right centrum semiovale lesion demonstrating diffusion restriction and patchy contrast enhancement. Differential diagnosis included posterior reversible encephalopathy syndrome, demyelinating disease, and progressive multifocal leukoencephalopathy. Lumbar puncture demonstrated non-inflammatory profile and negative EBV PCR, JC virus, oligoclonal bands, and autoimmune panel. There was no evidence of AML by CSF evaluation or MRI. Patient continued to have clinical deterioration and new left-sided weakness despite treatment with empiric steroids. Repeat MR brain showed increased extent of T2 hyperintensities, with resolved contrast enhancement. Brain biopsy of dominant lesion demonstrated multifocal perivascular and parenchymal demyelination with negative stains for JC virus and EBV, consistent with ADEM. The patient received IVIG, high dose steroids, and anakinra. At follow-up 10 months after admission, patient had no recurrence of symptoms, a normal neurologic exam, and stable to improving lesions on MRI.