Purpose: The purpose of this article is to investigate possible differences in effect between three types of masks in the acute treatment of cluster headache (CH). Patients and methods: Fifty-seven CH patients according to ICHD-II-criteria participated in a single-blinded, semirandomized, placebo-controlled, crossover inpatient study, and 102 CH attacks were treated with 100% oxygen delivered by demand valve oxygen (DVO), O2ptimask or simple mask (15 liters/min) or placebo delivered by DVO for 15 minutes. Primary endpoint: Two-point decrease of pain on a five-point rating scale within 15 minutes. Results: Only 10 CH patients had multiple attacks and reached the point of placebo. There were no significant differences between masks in the primary endpoints (p = 0.412). After 15 minutes 48% had a two-point decrease using the DVO compared to 45% with placebo (p = 0.867). After 30 minutes 68% were pain free or had pain relief using DVO and 45% by placebo (p = 0.061). The DVO was preferred by 62% compared to 5% and 33% for simple mask (p< 0.0001) and O(2)ptimask (p = 0.061). In the first attack the DVO was significantly better at achieving pain relief at 15 minutes (p = 0.018). Treatment with DVO or O(2)ptimask reduced the need for rescue medication compared to the simple mask (23%, 19%, 50%, respectively). No treatment-related adverse events were observed. Conclusion: The primary endpoint with pain relief at 15 minutes was non-significant; however, a post hoc analysis of the first attack significantly favored DVO. Further, therapy by O(2)ptimask and DVO resulted in a decreased need for rescue medication. We recommend that CH patients be offered DVO or O(2)ptimask before oxygen therapy is abandoned.