BACKGROUND: Tension-type headache is the most common form of headache and its chronic form, chronic tension-type headache (CTTH), is one of the most difficult to treat. The etiology of CTTH is not well understood, but is believed to be multifactorial and to vary among individuals. In the present study, the authors sought to identify common mechanisms of CTTH pathology. Empirical studies have implicated various immunomodulatory cytokines as mediators of chronic pain disorders, including CTTH. OBJECTIVES: To determine the role of peripheral cytokines and genetic factors in the development of CTTH. METHODS: A panel of cytokines hypothesized to play a role in the pathogenesis of CTTH was measured using cytometric bead arrays and ELISAs in 56 individuals with CTTH and 42 healthy control participants between 18 and 65 years of age. Results: Levels of interleukin (IL)-1ß were significantly elevated in participants diagnosed with CTTH relative to healthy controls, while IL-18 levels were found to be significantly elevated in men with CTTH. Because the levels of these immune mediators were increased in the apparent absence of injury or infection, the authors sought to determine whether genetic changes were responsible for fluctuations in cytokine levels. Polymerase chain reaction and restriction fragment length polymorphism analyses were used to determine individual genotypes at key single nucleotide polymorphism positions in the IL-1B gene. No association was observed between CTTH and single nucleotide polymorphisms in the IL-1ß gene. Conclusions: These findings suggest that increases in key proinflammatory cytokine levels are associated with CTTH and the pathology of the disorder involves sterile neurovascular inflammation. ©2013 Pulsus Group Inc. All rights reserved.