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Background: Observational studies have reported an association between obesity, as measured by elevated body mass index (BMI) in early adulthood and risk of multiple sclerosis (MS). However, bias potentially introduced by confounding and reverse causation may have influenced these findings. Therefore, we elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS. Methods and Findings: Employing a two-sample MR approach, we used summary statistics from GIANT and the International MS Genetics Consortium (IMSGC) the largest genome-wide association studies for BMI and MS, respectively (GIANT: N= 322,105, IMSGC: N=14,498 cases and 24,091 controls). 70 single nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 x 10-8 ) for BMI in GIANT (N=322,105) and were ascertained for MS risk in the IMSGC. The effect of each SNP on MS was weighted by its effect on BMI and estimates were pooled to provide a summary measure for the effect of increased BMI upon risk of MS. Our results suggest that increased BMI influences MS susceptibility, where a 1 standard deviation increase in genetically determined BMI (kg/m2 ) increased odds of MS by 41% (OR: 1.41, 95% CI: 1.20-1.66, p= 2.7 x 10-5 , I2=0%, 95% CI: 0-29). Sensitivity analyses, including MR-Egger regression, and the weighted median approach provided no evidence of pleiotropic effects. While these sensitivity analyses reduce the possibility that pleiotropy influenced our results, residual pleiotropy is difficult to exclude entirely. Conclusion: Genetically elevated BMI is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology. While obesity has been associated with many late-life outcomes, these findings demonstrate a more immediate and severe consequence of childhood and/or early adulthood obesity.