Objective To assess ictal adiponectin (ADP) levels before and after acute abortive treatment in women episodic migraineurs. Methods Peripheral blood specimens were collected from women episodic migraineurs before and after acute abortive treatment with sumatriptan/naproxen sodium vs placebo. Univariate and multivariate models were utilized to examine the relationship between serum total ADP (T-ADP), ADP oligomers (high molecular weight [HMW], middle molecular weight, and low molecular weight [LMW]-ADP), and ADP ratio levels and pain severity. Paired t-tests and random intercept longitudinal models were utilized to assess the mean changes in T-ADP, ADP oligomers, and ratios over time in treatment responders and nonresponders. Results Twenty participants (11 responders, 9 nonresponders) have been studied to date. In all participants, increases in the HMW: LMW ADP ratio were associated with an increase in pain severity. For every 1 point increase in the HMW: LMW ratio, pain severity increased by 0.22 (Confidence Interval [CI]: 0.07, 0.37; P =.004). In contrast, for every 0.25 μg/mL increase in LMW-ADP, pain severity decreased by 0.20 (CI: -0.41, -0.002; P =.047). In treatment responders, T-ADP levels were reduced at 30 minutes (12.52 ± 3.4; P =.03), 60 minutes (12.32 ± 3.2; P =.017), and 120 minutes (12.65 ± 3.2; P =.016) after treatment as compared with onset (13.48 ± 3.8). Additionally, in responders, the HMW: LMW ratio level was greater at pain onset (3.70 ± 1.9 μg/mL) as compared with nonresponders (2.29 ± 0.71 μg/mL), P =.050. Responders also showed a decrease in the HMW: LMW ratio at 60 minutes (2.37 ± 1.1; P =.002) and 120 minutes (2.76 ± 1.4; P =.02) after treatment as compared with onset (3.70 ± 1.9). These changes in responders remained significant after adjusting for covariates, including measured body mass index (m-BMI). Although nonresponders showed no significant changes in unadjusted T-ADP or ADP oligomer or ratio levels, the HMW: LMW ratio was increased in nonresponders after adjustments (P =.025). Conclusion In this pilot study of women episodic migraineurs, the HMW: LMW ADP ratio level was associated with migraine severity and predictive of acute treatment response. ADP and the HMW: LMW ratio of ADP represent potential novel biomarkers and drug targets for episodic migraine. © 2013 American Headache Society.