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Introduction: Preclinical studies have indicated insulin-like growth factor 1 (IGF1) as a novel therapeutic target in the treatment of migraines. We aimed to investigate the causal effect of circulating IGF1 levels on migraine risk using the two-sample Mendelian randomization method. Methods: A total of 431 independent variants from 363,228 unrelated individuals in the UK Biobank were used as genetic instruments for circulating IGF1 levels. Summary-level data for migraines were obtained from two independent studies with 10,536 and 28,852 migraine cases, respectively. Results: Mendelian randomization using inverse-variance weighting showed that increased IGF1 levels were significantly associated with decreased risk of migraines in both outcome datasets (odds ratio 0.905, 95% confidence interval 0.842–0.972, p = 0.006; odds ratio 0.929, 95% confidence interval 0.882–0.979, p = 0.006). Although some other robust Mendelian randomization methods did not demonstrate a significant association, no unbalanced horizontal pleiotropy was found by Mendelian randomization–Egger regression (p values for horizontal pleiotropy 0.232 and 0.435). The effect was confirmed in additional analyses including multivariable Mendelian randomization analyses. Conclusion: This two-sample Mendelian randomization study showed that genetically determined increased IGF1 levels are causally associated with decreased migraine risk. Future randomized controlled trials are warranted to confirm the benefits of IGF1 administration on migraines. [ABSTRACT FROM AUTHOR]