Previous research have implicated critical roles of systemic inflammation in the development of Multiple Sclerosis (MS). But the causal relationship between interleukins (ILs) and MS has not been fully elucidated. In this study, we applied Mendelian randomization (MR) approaches to address the causal associations between genetically determined circulating levels of ILs and the risk of MS. Genetic instruments for circulating IL-1 receptor antagonist (IL-1Ra), IL-2 receptor α subunit (IL-2Rα), IL-6, IL-16, IL-17, and IL-18 were obtained from recently published genome-wide association studies (GWAS). Summary-level data for MS were obtained from the International Multiple Sclerosis Genetics Consortium. MR analyses were performed using the R software (version 3.6.1, The R Foundation) and the TwoSampleMR package. Genetic predisposition to higher circulating levels of IL-2Rα were significantly associated with MS risk. The odds ratio (OR) was 1.22 (95% confidence interval [CI], 1.12-1.32; p < 0.001) per one standard deviation increase in circulating IL-2Rα levels. There was a suggestive association of circulating IL-1Ra with MS risk (OR, 0.94; 95% CI, 0.88-0.99; p = 0.027). The other ILs were not associated with the outcome. Our results indicated that circulating IL-2Rα was causally associated with risk of MS. Copyright © 2021 Lu, Wu, Zhang and Liao.