Nitric oxide plays an important role in the pathogenesis of migraine as well as tension-type headache. Studies suggest that the expression of molecules involved in the pathogenesis of headache, i.e., nitric oxide and interleukin, is influenced by apolipoprotein E (APOE) and is gene specific. Hence, we hypothesized that APOE polymorphism may be associated with migraine as well as tension-type headache.The study sample comprised of three groups: migraineurs, tension-type headache subjects as well as a healthy control group. A total of 50 subjects in each group were included after screening for the inclusion and exclusion criteria. None of the subjects was a blood relative of any other subject included in the present study. Their venous blood was drawn and stored at -20 degrees C. Genomic DNA extraction was performed with a commercial kit and simple sequence-specific primer PCR was performed to assess the APOE polymorphism. Data were analyzed with the help of SPSS V11.0 for Windows. chi(2) test and logistic regression analysis were run. The results of the study showed that APOE epsilon2 gene increases the risk of migraine as compared to the control group and the tension-type headache group (OR=4.85; 95% CI=1.92-12.72; P<0.001 and OR=2.31; 95% CI=1.08-4.94; P=0.01, respectively). Interestingly, APOE epsilon4 gene was protective against migraine as well as tension-type headache. This study shows that APOE epsilon2 gene increases the risk of migraine, while APOE epsilon4 gene is protective against migraine and tension-type headache. Further research is required to confirm the findings of the present study in a larger sample and to elucidate the role of APOE polymorphism in headache.