© 2015 American Academy of Neurology. Objective: To evaluate ictal adipokine levels in episodic migraineurs and their association with pain severity and treatment response. Methods: This was a double-blind, placebo-controlled trial evaluating peripheral blood specimens from episodic migraineurs at acute pain onset and 30 to 120 minutes after treatment with sumatriptan/naproxen sodium vs placebo. Total adiponectin (T-ADP), ADP multimers (high molecular weight [HMW], middle molecular weight, and low molecular weight [LMW]), leptin, and resistin levels were evaluated by immunoassays. Results: Thirty-four participants (17 responders, 17 nonresponders) were included. In all participants, pretreatment pain severity increased with every quartile increase in both the HMW:T-ADP ratio (coefficient of variation [CV] 0.51; 95% confidence interval [CI]: 0.08, 0.93; p 0.019) and resistin levels (CV 0.58; 95% CI: 0.21, 0.96; p 0.002), but was not associated with quartile changes in leptin levels. In responders, T-ADP (CV -0.98; 95% CI: -1.88, -0.08; p 0.031) and resistin (CV -0.95; 95% CI: -1.83, -0.07; p 0.034) levels decreased 120 minutes after treatment as compared with pretreatment. In addition, in responders, the HMW:T-ADP ratio (CV -0.04; 95% CI: -0.07, -0.01; p 0.041) decreased and the LMW:T-ADP ratio (CV 0.04; 95% CI: 0.01, 0.07; p 0.043) increased at 120 minutes after treatment. In nonresponders, the LMW:T-ADP ratio (CV -0.04; 95% CI: -0.07, -0.01; p 0.018) decreased 120 minutes after treatment. Leptin was not associated with treatment response. Conclusions: Both pretreatment migraine pain severity and treatment response are associated with changes in adipokine levels. Adipokines represent potential novel migraine biomarkers and drug targets.