The persistence and reactivation of classic viruses may be responsible for some chronic headache syndromes and their exacerbations. Persistent infections may selectively decrease neurotransmitter output. Alternatively, headache may be due to the viral-induced immune response. Lymphocytes secrete substances with CNS activity. Continuous antigenic stimulation may result in immune complexes, anti-idiotype antibodies, and autoimmunity. Our studies show an increased incidence of raised thyroid microsomal antibodies in patients with chronic benign daily headache or benign paroxysmal vertigo (a syndrome closely related to idiopathic headache syndrome). We detected oropharyngeal secretion of Epstein-Barr Virus by nucleic acid hybridization in 20 of 32 patients with the recently-defined syndrome of new, daily persistent headache and in only 4 of 32 age and sex-matched control patients. Based on these studies, we propose that chronic benign daily headache may be an auto-immune disorder with a persistent viral trigger.