Abstract Background/Introduction Patients with peripheral artery disease (PAD) are at risk of developing progressive symptoms leading to revascularization as well as major adverse limb events such as critical limb ischemia and amputation. Recently, two trials of PCSK9 inhibitors, which lower both LDL-C and Lp(a) have demonstrated reductions in MALE and peripheral revascularization. Whether this benefit is present for other LDL-C lowering therapies has not been well described. Purpose To evaluate whether LDL-C lowering with ezetimibe reduces the risk of adverse limb events. Methods IMPROVE-IT randomized 18,144 patients with acute coronary syndrome (ACS), including 1,005 with PAD, to ezetimibe or placebo on top of statin and followed for a median of 6 years. Two vascular specialists blinded to treatment allocation independently reviewed all adverse events to categorize limb outcomes including critical limb ischemia (CLI), and related amputation as well as progressive symptoms leading to lower extremity revascularization (worsening PAD). Total limb outcomes over follow up were compared by treatment groups using negative binomial regression and relative risks (RR) are presented. Results A total of 397 patients had worsening symptoms (in 346 PAD patients) and 43 developed CLI (in 36 patients) during follow up. The risk of total PAD events (CLI or worsening symptoms) was lower with ezetimibe versus placebo (RR 0.77, 95% CI 0.62 – 0.96, p=0.018) with a consistent trend for both components (Figure Panel A). When evaluating the relationship of achieved LDL-C at 1-month post-randomization and the risk of first PAD event, there appeared to a linear relationship extending to an LDL-C less than 25 mg/dL (Figure Panel B). Conclusion Further lowering of LDL-C with ezetimibe on top of statin therapy in patients with ACS was associated with a lower risk of adverse limb events over long-term follow up including CLI and progressive disease leading to revascularization. These data support the importance of intensive lipid lowering therapies in improving limb outcomes in patients with atherosclerotic vascular disease. In addition, these data support LDL-C as a treatment target for optimizing outcomes in patients with peripheral artery disease.Figure Panel AFigure Panel B