Alpha-lipoic acid (ALA) is known to lower insulin resistance (IR), which is common among migraineurs. To assess the effect of ALA on headache in migraineurs with IR, we performed an exploratory study on a cohort of patients with migraine, followed at our Headache Center. The 32 patients took ALA 400 mg b.i.d. for 6 months in addition to their on-going treatment. The percentage of patients with a reduction of at least 50% of the attacks was 0.53 (confidence interval [95% CI] 0.36–0.70) at 2 months, 0.56 (0.39–0.73) at 4 months, and 0.69 (0.53–0.85) at 6 months. The incidence rate ratio of attacks at 6 months versus baseline was 0.48 (0.43–0.53, P < .001), corresponding to a mean (95% CI) number of attacks of 5 (4–6) versus 11 (10–12). The number of days of treatment in the previous month was 7.7 (6.8–8.7) at baseline, 5.4 (4.6–6.2) at 2 months, 5.3 (4.5–6.1) at 4 months, and 4.3 (3.6–5.0) at 6 months. Baseline and 120-min glucose and insulin and quantitative insulin sensitivity check index (QUICKI) and the Stumvoll index did not change at 6 months versus baseline. This exploratory study shows that the administration of ALA may be associated with a reduction in the number of attacks and the days of treatment in migraineurs with IR. A randomized controlled trial is needed to test this possibility.