Background An association between migraine and stroke has been suggested for a long period, although conclusive evidence has not been reported. Several theories about hypercoagulability have been proposed for the association of ischemic stroke and migraine especially migraine with aura. This study aimed to assess blood coagulability in patients with migraine. Results Mean serum levels of protein S and anti-thrombin III were significantly lower in migraine patients compared to control subjects. Migraine patients showed abnormal MRI findings in the form of white matter hyper-intense lesions and ischemic foci compared to healthy controls. A significant negative correlation was detected between serum protein C level and intensity of migraine headache. Also, a significant correlation was found between deficient serum protein S and abnormal findings in brain MRI. Serum protein C deficiency is an independent predictor for migraine intensity grade. Conclusions There is an association between migraine and hypercoagulability, which may indicate increased risk of cerebral ischemic events in migraine patients and suggest adding prophylactic therapy to the management strategies of such patients.