BACKGROUND: Serotonin transporter protein (5-HTT) is a key modulating protein in synaptic serotonergic neurotransmission. Among serotonin gene-linked polymorphism, the promoter, located in the regulatory region of the 5-HTT gene linked polymorphic region (5-HTTLPR), has two alleles with different transcriptional efficiencies. The harm avoidance (HA) personality dimension, estimated by a self-administered tri-dimensional personality questionnaire (TPQ), has been postulated to be heritable and associated with serotonergic neurotransmitter activity. We therefore investigated 5-HTTLPR and HA in patients with chronic tension type headache and migraine. METHODS: We amplified the 5-HTTLPR by means of polymerase chain reaction and performed genotype polymorphism analyses and investigated the serotonin related personality trait by evaluating the HA dimension in tridimensional personality questionnaire (TPQ) in 107 patients with chronic tension type headache (CTH) and in 115 patients with migraine without aura (MWOA) and in 100 healthy controls. RESULTS: We found an excess frequency of the short allele and a different genotype distribution in patients with CTH. S/S genotype frequency was significantly higher in patients with CTH (76%) than in those with MWOA (61%) and controls (59%; P=0.18). TPQ questionnaires showed significantly higher HA scores in both CTH (21.4 +/- 6.3) and MWOA (21.3 +/- 7.2) compared with controls (16.31 +/- 6.1). CONCLUSIONS: This suggests a serotonergic activity might be involved in development of CTH and MWOA and 5-HTTLPR might be one of the genetically contributing factors, especially in patients with CTH through presence of the S allele.