The harlequin sign or syndrome is a rare cranial autonomic condition characterized by unilateral diminished flushing and sweating of the face (and sometimes arm), in response to heat or exercise. It results from autonomic, mainly sympathetic dysfunction. Although the idiopathic form is the most common, underlying structural abnormalities in the head, neck, and thorax need to be excluded. Here, we describe the first case of the combination of primary cluster headache and the harlequin syndrome in a 49-year-old female patient. The patient presented with a first bout of cluster headache with persisting Horner syndrome and new harlequin sign after the bout. Additional neuroimaging did not reveal underlying pathologies. This report provides an overview of cases from the literature and then discusses the association between primary headaches and the harlequin syndrome. Relevant anatomy, diagnostic tools, and therapeutic options are all considered. This case reports a rare combination of cluster headache and harlequin sign that warrants further testing to exclude pathology in the brain, neck or mediastinum. It also illustrates the underlying anatomy and physiology of the autonomic nervous system. © 2020 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.