Histamine release and leukotrienes (LTB4 and LTC4) production from circulating basophil have been studied in 13 patients with episodic cluster headache (CH) during the remission phase of symptoms, and in 9 normal subjects. Cell suspensions of basophils were stimulated with scalar dilutions of anti-IgE, f-met-peptide and Ca2+ ionophore A23187. Histamine was measured by an automated fluorimetric method; LTB4 and LTC4 with RIA in individual cases, and with Reverse-Phase HPLC in the two pools obtained from the supernatants of CH patients and controls. Mean values of histamine release in patients with CH were significantly lower when compared to those obtained in control subjects after stimulation with anti-IgE at the three dilutions used. LTC4 mean levels measured in CH patients were significantly lower than those of supernatants from controls after stimulation with 0.05 gamma/ml of A23187. A reduction of LTC4 and LTB4 levels in CH patients was also observed in R-P HPLC, which showed different elution patterns in the two groups. The histamine release in individual cases was related to leukotriene production: LTC4 levels were significantly (p less than .05) higher in "high histamine releasers" than in "low histamine releasers". Our results indicate that CH patients have complex abnormalities of histamine release and of leukotriene production during the painless phase of the disease.