Plasma methionine-enkephalin (MET) levels in migraine patients, either during an attack or when pain-free, are statistically significantly higher than in matched controls; this is also true when comparing the classical and nonclassical migraine subpopulations with the control group. Individual patients consistently presented lower MET plasma concentrations in the pain-free period than during the acute headache, with some subjects showing values falling within the range of controls. Platelet neuropeptide content was similar in patients and controls, irrespective of plasma MET levels. These results indicate that increased plasma MET concentrations are associated with the occurrence of a migraine episode and suggests that they are not a constant characteristic of migraineurs.