Migraine patients, either during an attack or when pain-free, have significantly higher platelet-rich and platelet-poor plasma methionine-enkephalin levels than healthy race- and sex-matched and age-comparable controls. Although we did not observe differences in the platelet-rich samples between the patients subgroups, platelet-poor samples had higher peptide levels during a pain-free period than the values obtained for the patients during a migraine episode. Similarly, platelet-rich samples obtained from controls and patients during an attack had higher methionine-enkephalin levels than their corresponding platelet-poor plasma samples. These results provide new evidence supporting the involvement of the endogenous peptides in the etiology of migraine headache and suggest that plasma methionine-enkephalin levels could serve as a biological marker for this condition.