Acute Necrotizing Encephalopathy of Childhood (ANE) is a rare form of acute parainfectious encephalopathy occurring most commonly in Eastern countries. ANE has a variable clinical spectrum with a homogenous biochemical, neuroimaging and neuropathological profile among the cases described in the literature. This entity has a variable prognosis with a mortality rate of up to 30% of cases. We describe the case of a four-year-old boy who was diagnosed with ANE several days after receiving a varicella immunization and following the development of a nonspecific viral febrile illness associated with acute gastroenteritis, seizure episodes and rapid deterioration in the level of consciousness. Laboratory analysis was remarkable for an acute marked elevation of serum aminotransferases without associated hyperammonemia and CSF analysis did not revealed pleocytosis. There was evidence of bithalamic-restricted diffusion on brain MRI as well as additional bilateral lesions on cerebellar hemispheres and vermis, which are part of the radiologic diagnostic criteria for this condition. Clinical, laboratory and radiological findings in this case pointed to the diagnosis of ANE and served to differentiate it from other similar syndromes that must be considered in the differential diagnosis. In addition to the marked improvement from initial neurological deficits and surviving despite a reported 30% mortality, the significance of this case relies on the fact that it represents an atypical disease in Western countries and the report of an association with varicella immunization.