Corticosteroids appear to be the most rapid-acting of the prophylactic drugs used in the treatment of cluster headache (CH). These agents are frequently employed as a short-term regimen to induce clinical remission. In this study, we assessed in an open fashion the effect of high dose methylprednisolone (MPD) in a group of 13 patients with episodic CH (3 females and 10 males). On the 8th day of the active period, MPD was administered intravenously at the dose of 30 mg/kg body weight, as a 3-h infusion in saline. The attack frequency was followed for 7 days. The mean daily attack frequency before MPD administration was statistically different from that reported after treatment (respectively: 1.38 ± 0.42 and 0.83 ± 0.78; P = 0.05 Student's t-test). The mean interval between MPD administration and the occurrence of the first subsequent attack was 3.8 ± 2.2 days (range: 2–7 days). Only 3 (23%) of 13 patients experienced a complete headache remission. No significant side-effects were noted after MPD administration. These data further demonstrate that in most patients with episodic CH, high-dose systemic steroid administration may invariably interrupt attack recurrence for a few days, but is ineffective in maintaining complete clinical remission. This study also suggests that MPD administered as a solitary dose does not provide any advantage above prednisone in CH treatment.