BACKGROUND: Approximately one half of the patients with chronic daily headaches report a regular use of analgesics, making it an important issue for public health matters. However, factors contributing to the dependency and overuse of analgesics for chronic tension type headaches have been little understood. We investigated the role of chronic analgesics exposure in the natural course and clinical phenotype of headaches in patients with chronic tension type headaches. We also evaluated genetically determined innate factor that could exert a profound influence on a development of analgesics overuse using a serotonin transporter protein polymorphism and serotonergically related harm avoidance (HA) personality dimension. METHODS: We analyzed the headache characteristics using a standardized questionnaire from 38 patients with chronic tension type headache with analgesics overuse (CTTH-AO), from 40 patients with chronic tension type headache without analgesics overuse (CTTH-NO) and from 100 healthy controls. We performed the serotonin transporter protein gene linked to the polymorphic region (5-HTTLPR) genotype, polymorphism analyses and investigated the serotonin related personality trait by evaluating the HA dimension in tri-dimensional personality questionnaires (TPQ). RESULTS: We found a significantly higher pain intensity and disability score in patients with CTTH-AO. Most of the patients with CTTH-AO used analgesics compound containing caffeine for pain relief. S/S genotype frequency was significantly higher in patients with CTTH-AO than in those with CTTH-NO and controls. TPQ questionnaires showed significantly higher HA scores in both CTTH-AO and CTTH-NO than in controls. CONCLUSIONS: This suggests a serotonergic activity might be involved in development of analgesics overuse in chronic tension type headaches, and 5-HTTLPR might be one of the genetically contributing factors.