The hallmarks of Reye's Syndrome which include hyperammonemia, elevated liver enzymes and progressive encephalopathy, have been associated with certain inherited metabolic disorders, thus, current recommendations are to screen atypical Reye's Syndrome cases for defects in amino acid, organic acid and carbohydrate metabolism. Hereditary isolated glucocorticoid deficiency(HIGD) is characterized by undetectable cortisol levels, normal mineralocorticoids and elevated ACTH levels while molecular analysis has demonstrated a point mutation in the MC2R gene of the ACTH receptor in some cases. The presenting symptoms of HIGD in early childhood have been hypoglycemia and/or hyperpigmentation. A 3 5/12 year male with expressive language delay and at least one previous unexplained episode of ataxia had a metabolic evaluation which yielded normal levels of plasma carnitine and non diagnostic urine for amino and organic acids. At 3 10/12 years he presented with 24 hours of vomiting followed by diarrhea and seizures. No aspirin had been given. He was lethargic and stimulation produced asymmetric decorticate posturing. Initial glucose was 28 mg/dl, maximal AST 163 U/L (<58), and NH4 126 μmol/L (10-47). Stool for Rotavirus was positive. The urine contained 30H butyric acid, adipic and suberic acids. Neurologic findings were not immediately reversed by normalization of blood glucose nor administration of dexamethasone. The EEG was reported to be consistent with diffuse cerebral dysfunction of a moderate degree compatible with State I to II Reye's Syndrome. Recovery occurred over 24-48 hours. At 4 2/12 years, after a seizure with ketotic hypoglycemia, cortisol was undetectable with ACTH of 2655 pg/ml(normal adult 9-52) while electrolytes and plasma renin activity were normal. There was no cortisol response to exogenous ACTH stimulation. Genomic DNA was extracted from peripheral blood lymphocytes and amplified by PCR with primers flanking the entire MC2R coding region. Single stranded DNA was generated by PCR and sequenced which revealed a homozygous Ser-74-Ile mutation of the MC2R gene. Two cases have been previously described with a postmortem diagnosis of HIGD following a Reye-like episode. This is the first case of Reye's Syndrome associated with HIGD due to an MC2R gene mutation. Determination of a cortisol level is recommended as part of the evaluation for metabolic disorders associated with Reye's Syndrome.