There is considerable evidence suggesting that cytokines play important roles in pain and in mediating neurovascular inflammation associated with migraine headaches. Although consensus exists to recommend topiramate (TPM) for migraine prevention, the mechanism of action in this regard is unknown. We measured serum interleukin-6 (IL-6) levels in 66 migraine patients. Of these patients, 23 (34.9%) were taking TPM for migraine, and 43 (65.1%) were not. The IL-6 levels were compared with those of healthy controls without migraine, from the population living in the same region. The mean IL-6 levels in migraine patients taking TPM and patients who did not were 67.06 ± 92.09 pg/mL and 44.09 ± 59.19 pg/mL, respectively (P > 0.05). The IL-6 levels were higher in the patients taking TPM. The IL-6 level in the controls was 8.60 ± 7.36 pg/mL, which was significantly lower than the patient group using TPM (P = 0.001). Our results show that, although IL-6 may be involved in pain induction or inflammatory mechanisms of migraine attacks, the serum IL-6 level was not reduced in migraine patients receiving TPM therapy. In conclusion, we found high IL-6 levels in migraine patients both with and without TPM therapy, suggesting that high IL-6 levels during pain-free periods could be a conditioning factor, making patients more vulnerable to pain attacks in chronic migraine. Further studies investigating the possible mechanism of TPM in migraine are needed.