Peripheral immunity has been observed to be associated with amyotrophic lateral sclerosis (ALS) clinically, but whether there exist causal association and the effect direction is controversial and elusive. The objective of this study is to explore the causal relationship of peripheral immune cell traits including total leukocytes count, monocyte count, neutrophil count, eosinophil count, basophil count, and lymphocyte count on ALS risk. We conducted a two-sample Mendelian randomization analysis to estimate the causal effects. Significant single nucleotide polymorphisms from genome-wide association study on human blood cell traits were utilized as exposure instruments and summary statistics of ALS as outcome. The causal relationship was evaluated by inverse variance weighted, MR Egger regression and weighted median methods, and further verified by extensive sensitivity analyses. We found that genetically determined one standard deviation increase in total leukocytes count was associated with lower risk of ALS (OR: 0.906, 95% CI: 0.842-0.974, P: 0.007) after Bonferroni correction, and increased neutrophil count showed suggestive association with reduced ALS risk (OR: 0.926, 95% CI: 0.858-1.000, P: 0.049). The results were robust under all sensitivity analyses. Our study reveals a genetic predisposition to higher peripheral leukocytes with an inverse causal effect on the risk of ALS, highlighting the important role of peripheral immunity in the development of ALS.