In five patients affected by classical migraine a longitudinal study was performed, dealing with the in vitro parameters of platelet aggregation, during prodromal, attack, post-attack and interval phases. These patterns were compared with the analysis of blood leukotrienes, carried out by use of analytical reversed phase HPLC. Presence of leukotriene C4 (LTC4) during prodromal and attack phases, corresponded to a transient inhibition of epinephrine-induced aggregation. Recovery towards normal or increased values of platelet aggregation occurred during both post-attack and interval phases, which were accompanied by the presence in blood of 5–12 di-hydroxyeicosatetraenoic acid (5–12 DHETE) and/or leukotriene B4 (LTB4) respectively, and by their subsequent metabolic breakdown products. Hypotheses on the role of leukotrienes in the pathogenesis of migraine are discussed.