Alpers-Huttenlocher syndrome, considered a mitochondrial disease, combines encephalopathy and liver failure. An 11-year-old boy with Alpers-Huttenlocher syndrome underwent conventional MR imaging, diffusion-weighted imaging, and proton MR spectroscopy. Diffusion-weighted imaging showed cytotoxic edema interpreted as acute-phase encephalopathy. MR spectroscopy revealed a lactate peak in the cortex that appeared abnormal on diffusion-weighted images, possibly representing respiratory deficiency with anaerobic metabolism. MR spectroscopy proved to be more sensitive regarding lactate detection than did neurometabolic examination of serum and CSF. A reduced N-acetylaspartate-creatine ratio was detected in both the cortex that appeared abnormal and the cortex that appeared normal on the diffusion-weighted images, indicating neuronal damage that was widespread, even beyond the boundaries of conventional MR imaging changes.