Enkephalins are co-released with catecholamines from sympathetic terminals in the heart and have recently been identified to play an important adaptive metabolic signalling role in cardioprotection against ischemia or hypoxia-related injury. The study aims were: a) to determine the myocardial levels of methionine-enkephalin in tetralogy of Fallot; and b) to correlate myocardial content of methionine-enkephalin with the extent of arterial oxygen desaturation. Tissue samples obtained during surgical correction of tetralogy of Fallot were assayed via radioimmunochemistry for their methionine-enkephalin content. Arterial oxygen saturation was measured on admission for surgery. The main finding was evidence of greater methionine-enkephalin content in right ventricles of 21 patients suffering from cyanotic spells (cyanotic spells: 2418±844 pg/g wet weight tissue, n=6; no spells: 1175±189pg/g wet weight tissue, n=15, p=0.045). A negative correlation was evident between the arterial oxygen saturation and myocardial methionine-enkephalin content. In conclusion, myocardial methionine-enkephalin levels increase with the severity of cyanosis in congenital cardiac disease. Opioids, particularly methionine-enkephalin, the key bioactive end product of proenkephalin, may play an important adaptive role in hypoxia-related adrenergic over-activity.