Background and purposeTo clarify the causal associations of interleukin‐1 receptor antagonist (IL‐1ra) and interleukin‐2 receptor alpha subunit (IL‐2rα) with the risk of amyotrophic lateral sclerosis (ALS).MethodsA two‐sample Mendelian randomization study design was employed. Single‐nucleotide polymorphisms associated with IL‐1ra (n = 2) and IL‐2rα (n = 1) at the genome‐wide significance level were used as unbiased instrumental variables. Summary‐level data for ALS were obtained from Project MinE, an international collaboration consortium with 12 577 ALS cases and 23 475 controls of European descent.ResultsGenetic predisposition to higher levels of IL‐1ra was significantly associated with lower odds of ALS. For a 1‐SD increase of circulating IL‐1ra levels, the odds ratio of ALS was 0.64 (95% confidence intervals, 0.46–0.88; P = 0.005). There was a borderline inverse association between IL‐2rα levels and ALS (odds ratio, 0.91; 95% confidence intervals, 0.83–1.00; P = 0.058).ConclusionsInterleukin‐1 receptor antagonist levels were inversely associated with ALS, suggesting that interleukin‐1 inhibitors may lower the risk of this always fatal disease. The role of IL‐2rα levels in ALS needs further verification in causal inference studies with larger sample sizes.