Propionic acidemia is a disorder of branch-chain amino acid and odd-chain fatty acid metabolism. The clinical features typically begin shortly after birth, with rare cases presenting in young adulthood. This disorder most commonly is characterized by episodic decompensations with dehydration, lethargy, nausea, and vomiting as well as a risk for neurologic sequelae. The defect is in the propionyl-CoA carboxylase enzyme with a resultant accumulation of toxic organic acid metabolites. Neuropathologic findings in this inborn error of metabolism have not been extensively characterized but include white matter spongiosis in neonates and a variable appearance in older children. We describe the pertinent literature on the neuropathology of propionic acidemia and a case report of a 4-year-old girl who had widespread gray matter vacuolization at postmortem examination. Although a previously unreported finding in propionic acidemia, diffuse gray matter vacuolization has been described in other fatty acid metabolic disorders.