Reports have indicated that patients with migraine have abnormalities in platelet function and in the metabolism of vasoactive monoamines. On the basis of these findings, a number of compounds with a stabilizing effect on the level of free vasoactive monoamines in plasma or with anti-platelet effects have been evaluated with regard to their prophylactic effect in migraine. Femoxetine, a new phenylpiperidine derivative and a potent selective serotonin uptake inhibitor, has been suggested as a useful prophylactic drug in migraine. The present studies were designed to evaluate platelet function and blood serotonin levels in patients with migraine before and during femoxetine treatment. During the treatment of 11 patients with migraine with 300 mg femoxetine daily, blood serotonin decreased from 0.17 +/- 0.06 microgram/ml (mean +/- SD) to 0.06 +/- 0.02 microgram/ml. In 8 patients treated with 300 mg femoxetine daily for 12 weeks, 14C-serotonin uptake into platelets in vitro was reduced significantly. Unlike most drugs used in migraine prophylaxis, femoxetine did not influence platelet aggregation in vitro. The demonstration of a certain prophylactic effect of femoxetine in some patients lends support to theories of a serotonin involvement in the pathogenesis of migraine. It does not, however, exclude the possibility of a platelet abnormality as the primary cause of migraine. A hypothesis combining the 2 theories is put forward.