We designed this multicenter study to evaluate the abnormalities related to the mast cell activation during attacks in a large group of migraineurs and to compare the findings both with episodic tension type headache (ETTH) and matched healthy control subjects. After the evaluation of diagnostic criteria, 213 subjects were included in this study after giving consent. Of all 146 subjects (67.8%) were migraineurs, 38 (19.4%) were ETTH patients and 29 others were healthy controls matched according to age and sex. Immunological screening showed significantly high ratios of IL-beta, IL-2, IL-6 and TNF-alpha in the migraine group compared to ETTH (16.6% vs 10.5%, 20.0% vs 5.3%, 13.8% vs 2.6% and 15.9% vs 5.3%, respectively) and to the healthy controls. Logistic regression analysis showed that only duration of headache has an important effect on having IL-2 abnormality (Exp-B: 0.322, 95% CI: 0.151-0.688, p=0.003) in patients with migraine. There was no important effect of clinical variables on serological abnormalitites or each other. In conclusion, our multicenter clinical and laboratory based study suggests that primary headache disorders (migraine and ETTH) are associated with atopic changes and they might share the inflammatory mechanism (pro-inflammatory as well as anti-inflammatory cytokine abnormalities) during headache attacks.