<p><strong>Objective:</strong> Patients with diabetes have an increased risk for lower-limb amputation (LLA) but biomarkers to assess risk of LLA are lacking. Adrenomedullin (ADM) is a vasodilator peptide that also plays a role on fluid and electrolyte homeostasis in the kidney, increasing natriuresis and diuresis. ADM was shown to be associated with cardiovascular and renal events in diabetes, but it was not investigated in terms of LLA risk. We investigated the hypothesis that ADM is associated with LLA in people with type 2 diabetes.</p> <p><strong>Research Design and Methods: </strong>We studied 4375 participants of DIABHYCAR and SURDIAGENE cohorts (men 68%, mean age 66 years, mean duration of diabetes 12 years, median follow-up 5.3 years). Plasma MR-proADM (a surrogate for ADM) was measured by immunofluorescence. Five SNPs in the <em>ADM</em> gene region were genotyped.</p> <p><strong>Results:</strong> LLA requirement during follow-up by increasing tertiles of plasma MR-proADM distribution was 1.0% (T1), 2.3% (T2) and 4.4% (T3) (p<0.0001). In Cox multivariate analysis, adjusted hazard ratio (95%CI) for LLA was 4.40 (2.30–8.88; p<0.0001) for T3 vs. T1. Moreover, MR-proADM significantly improved indices for risk stratification of LLA. Four SNPs were associated with plasma MR-proADM concentration at baseline and with LLA during follow-up. Alleles associated with higher MR-proADM were associated with increased LLA risk.</p> <p><strong>Conclusions:</strong> We observed associations of plasma MR-proADM with LLA and of <em>ADM</em> SNPs with plasma MR-proADM and with LLA in people with type 2 diabetes. This pattern of Mendelian randomization supports the causality of the association of ADM with LLA.</p>