Serotonin (5-HT) binds in a saturable and specific manner to high affinity binding sites present on the surface of human mononuclear cells. The serotonin binding to mononuclear cells has been assayed in patients with migraine, during and outside the crisis period. In these patients, unlike the episodic cluster headache patients that show a constant trend, the results are variable. This variability may depend on the fluctuation of 5-HT levels in the blood, during and after the crisis. A possible explanation for these observations is that at the beginning of the crisis the binding of 5-HT is still similar to the normal level. As the crisis goes on, there is at first an increase in 5-HT binding that saturates all the available sites and a subsequent phenomenon of desensitization, with a loss of high affinity sites. Further investigations are needed in order to assess whether or not the mononuclear cell functions are affected by the modifications of the binding of 5-HT, thought to be a regulatory molecule.