Acute necrotizing encephalopathy and acute disseminated encephalomyelitis are 2 rare types of acute postinfectious encephalopathy in children. Acute necrotizing encephalopathy is characterized by multiple symmetric lesions in the thalami, putamena, cerebral and cerebellar white matter, and brainstem. Acute disseminated encephalomyelitis is an immune-mediated demyelinating central nervous system disorder that predominantly affects the white matter. Diffusion magnetic resonance imaging is sensitive to measuring water diffusion in the central nervous system in human and animal models. Recent studies have demonstrated that by using an analytical approach to directional diffusivity-derived parameters, the axial diffusivity and the radial diffusivity, one can assess the extent of axonal or myelin injury in the central nervous system white matter. We applied directional diffusivity to acute necrotizing encephalopathy, acute disseminated encephalomyelitis, and control subjects correlating with neuropathology findings. In acute necrotizing encephalopathy, axonal injury without demyelination, noted on biopsy samples of brain tissue, was suggested by a decreased apparent diffusion coefficient, unchanged fractional anisotropy, and decreased axial and radial diffusivity. In acute disseminated encephalomyelitis, an increased apparent diffusion coefficient, decreased fractional anisotropy, unchanged axial diffusivity, and markedly increased radial diffusivity compatible with active inflammatory demyelination were noted, consistent with tissue biopsy sample neuropathology. In conclusion, diffusion tensor parameters can potentially depict more microstructural changes than conventional magnetic resonance imaging in postinfectious encephalopathy in children.