In order to obtain data regarding peripheral levels of β-endorphin in head pain syndromes, we evaluated the plasma β-endorphin secretory pattern in 12 adult male patients suffering from cluster headache. Blood samples were drawn every 2 hours for a 24-hour period, and in addition at 30-minute intervals for 120 minutes during cluster attacks. The same sampling was repeated during an asymptomatic period. Cluster headache patients showed no significant β-endorphin circadian rhythm and a delayed acrophase during cluster periods compared with that recorded in the remission period and in normal subjects. Eighteen cluster headache attacks were recorded during the study day, 13 (72%) of which were followed by a significant increase in β-endorphin levels. No correlation was found between β-endorphin maximum net increase and intensity and/or duration of pain. These data suggest the hypothesis of a temporary alteration of β-endorphin circadian secretion, probably related to involvement of neural structures controlling biorhythm pacemakers.