Opioid system hypofunction has been postulated in cluster headache (CH) on the basis of reduced opioid levels found in the cerebrospinal fluid (CSF). In this study beta-endorphin levels were monitored in the peripheral blood mononuclear cells of 65 episodic CH patients (32 in remission and 33 in cluster period) and 50 healthy controls. Beta-endorphin levels were significantly lower than controls in CH patients experiencing both phases of the illness (ANOVA, p < 0.0001). The persistence of this abnormality during pain-free remission suggests a primary alteration in the regulation of beta-endorphin in peripheral blood mononuclear cells. We speculate that these findings reflect reduced CNS levels of beta-endorphin in CH.