Alpers-Huttenlocher syndrome (AHS) is a rare mitochondrial disorder of childhood onset that is characterized by progressive encephalopathy and hepatopathy. MRI studies are rare and have not added substantial information to the pathogenesis of the encephalopathy. Diffusion-weighted MRI (DWI) and MR spectroscopy (MRS) were used in a patient with AHS during acute clinical deterioration and after improvement. DWI detected signal hyperintensity in several brain areas not restricted to any vascular territory. MRS revealed an unequivocal lactate peak and a reduced N-acetyl-aspartate-creatinine (NAA/Crea) ratio. DWI signal hyperintensity was correlated with neurologic symptoms and decreased after clinical improvement. Potentially reversible neuronal cytotoxic edema resulting from acute impairment of mitochondrial function is strongly suggested to be an important pathogenetic mechanism in AHS encephalopathy.