Objective:. Coffee consumption has been suggested to decrease the risk of multiple sclerosis (MS). In this study, we aim to investigate the causal effect of coffee consumption on risk of MS by Mendelian randomization (MR) approaches. Methods:. Through a genome-wide association study including 375,833 participants from UK Biobank, we obtained single-nucleotide polymorphisms (SNPs) associated with habitual coffee consumption (P < 5 × 10−8). Summary-level data for MS were obtained from a meta-analysis, incorporating 14,802 subjects with MS and 26,703 healthy controls of European ancestry, which was conducted by the International Multiple Sclerosis Genetics Consortium. MR analyses were performed using inverse-variance-weighted method, weighted median estimator, and MR-Egger regression. Additional analyses were further performed using MR-Egger intercept and Cochran's Q statistic to verify the robustness of our findings. Results:. Nine coffee-associated SNPs were selected as instrumental variables. We failed to detect a causal effect of coffee consumption on MS risk (odds ratio, 1,00; 95% confidence interval, 0.98-1.01; P = 0.48). In the main MR analysis. Consistent results were yielded in sensitivity analyses using the weighted median and MR-Egger methods, and no horizontal pleiotropy (P = 0.49) was identified. Conclusion:. Our MR results indicated that coffee consumption might not be causally associated with risk of MS occurrence. Further well-designed genetic-epidemiological studies investigating the effect of coffee intake on the disease course, such as relapse and progression, are warranted. © 2020 Elsevier B.V.