All childhood liver biopsy specimens from The Cincinnati Children's Hospital Research Foundation which had been prepared for light and electron microscopy were reviewed to identify biopsies from children with salicylate intoxication. Only two cases of primary salicylate intoxication were identified. The histopathology and ultrastructural pathology were compared to that in two cases of Reye's syndrome which were selected because they had been treated with salicylates and had comparable serum salicylate concentrations at the time of liver biopsy. Liver biopsy specimens from the cases of salicylate intoxication were nearly normal by light microscopy. Lipid accumulation was minimal, and the content of glycogen and succinic acid dehydrogenase activity was normal. Mitochondria and peroxisomes appeared normal. Light and electron microscopy of liver specimens from the two cases of Reye's syndrome revealed swollen hepatocytes with microvesicular fat and central nuclei. Glycogen content and succinic acid dehydrogenase activity were diminished. All hepatocyte mitochondria were enlarged, pleomorphic, and had an expanded matrix and no mitochondrial dense bodies. The histopathology and ultrastructural pathology of liver biopsy specimens in salicylate intoxication were different from those in Reye's syndrome. In children in whom the diagnosis of Reye's syndrome is obscure, liver biopsy with electron microscopic examination is necessary for definitive diagnosis.