Levels of beta-endorphin in peripheral blood mononuclear cells have been studied as a new approach to investigating opioid tone in migraine and tension-type headache. Sixty-one patients with migraine without aura, 39 with migraine with aura and 23 with episodic tension-type headache were compared with 37 healthy controls. Peripheral blood samples were taken from patients not enduring headache attacks and not undergoing prophylactic treatment. A significant reduction in peripheral blood mononuclear cell beta-endorphin concentrations was observed in migraine patients with and without aura, but not in tension-type headache patients. Altered transmitter modulation to peripheral blood mononuclear cells may be the cause of this alteration, which could be part of a more diffuse opioid system derangement in migraine subjects.