Migraine is a common debilitating neurovascular disorder. The vascular genes ACE and MTHFR are involved in alterations in vascular endothelium and are suggested to play a role in migraine susceptibility. The aim of our study was to find out the role of ACE ID (rs no. 4646994) and MTHFR C677T (rs no.1801133) polymorphisms in genetic susceptibility of migraine in north Indian population. A total of 150 migraine patients, 220 non-migraine headache patients (Disease controls) and 150 age-sex matched normotensive healthy controls were enrolled for our study. DNA was isolated from peripheral blood leucocytes, and subjected to amplification using specific primers and genotyped using PCR (in case of ACE ID) or PCR-RFLP (in case of MTHFR C677T) methods. chi(2) test was applied for the analysis of genotypic and allelic distributions. Logistic regression analysis was used to find out contribution of genetic polymorphisms to the risk of disease. ACE DD genotype showed significant association in migraine patients with aura (MA) but a marginal significance in female MA patients in comparison with healthy controls. No significant differences in genotype and allelic frequencies of MTHFR C677T polymorphism were found on comparing migraine patients with either disease controls or healthy controls. In contrast, we found synergistic role of ACE (DD)*MTHFR (CT) interaction, showing a positive association in total migraine with aura patients as well as female migraine patients with aura when compared with healthy controls.