Aim To explore the potential causal association between galectin-1 (Gal-1) levels and atherosclerosis (As). Methods Single nucleotide polymorphisms (SNP) associated with Gal-1 served as instrument variables (IV), and the causal association between genetically predicted Gal-1 levels and As was analyzed by the two-sample Mendelian randomization (MR) method. Results Inverse variance weighted (IVW) results showed that genetically predicted Gal-1 levels were positively associated with risk of peripheral As and other As type (excluding cerebral artery, coronary artery, and peripheral artery) after Bonferroni adjustment (OR=1.6,5%CI:1.05～1.27, P＝0.002; OR=1.6,5%CI:1.12～1.20, P＝ 4.11E－17). There was no evidence supporting the causal association between Gal-1 and either coronary As or cerebral As (OR=1.2,5%CI:0.91～1.14, P＝0.765; OR=1.0,5%CI:0.94～1.29, P＝0.220); After Meta-analyzed the MR estimates of As outcomes at different sites, the results showed that genetically predicted Gal-1 levels were positively associated with As risk (OR=1.2,5%CI:1.06～1.19). ConclusionThe study suggests that genetically predicted Gal-1 level is causally associated with As risk, and Gal-1 is a potential target to prevent the occurrence of As.