The pressure pain threshold of 30 patients affected by tension-type headache was assessed and the values compared with those of a group of 30 age-matched control subjects. In the patient group, pressure pain threshold values were related to the blood cell concentration of some neurotransmitters which are considered to be involved in the genesis and modulation of pain (beta-endorphin levels in peripheral blood mononuclear cells [PBMCs], substance P and serotonin concentrations in platelets). The pressure pain threshold was significantly lower in tension-type headache patients than in control subjects (P < 0.0006). Significantly lower levels of beta-endorphins in PBMCs and substance P in platelets, as well as significantly higher levels of serotonin in platelets were found in tension-type headache patients compared to the control subjects (P < 0.0001). A significant positive correlation was found between pressure pain threshold values and beta-endorphin levels in both control and patient groups (P < 0.0001). On the contrary, a statistically significant negative correlation was evident between pressure pain threshold values and substance P levels in platelets in both patients and control subjects (P < 0.01 and P < 0.001, respectively). In both groups, there was a negative correlation between beta-endorphins in PBMCs and substance P in platelets (patients P < 0.02, controls P < 0.001). The findings of altered beta-endorphin levels in blood mononuclear cells and substance P levels in platelets could be the peripheral biochemical reflection of the low pressure pain threshold values in tension-type headache patients, and support the hypothesis of an impairment of the antinociceptive systems in this form of headache.