Purpose <p>The prevalence of severe vascular calcification in patients with Chronic Limb-Threatening Ischemia (CLTI) hinders the outcome of endovascular interventions and increases the risk of amputation and death. Intravascular lithotripsy (IVL) is a safe and effective treatment that promotes revascularization; however, large-scale data on its long-term effectiveness are lacking. The Chronic Limb-Threatening Ischemia treated with Intravascular Lithotripsy Observational Study (CALCIO) aims to address this shortcoming by assessing the real-world, long-term outcomes of IVL in a large cohort of patients with CLTI.</p> Methods <p>CALCIO is a worldwide, multicenter, prospective cohort study designed to follow for 2&#xa0;years 400 participants treated with the Shockwave Medical IVL System. Eligible patients, adults (≥ 18&#xa0;years) with CLTI (Rutherford category ≥ 4) and calcified femoro-popliteal and/or crural lesions visible on fluoroscopy, are recruited upon providing informed consent. The primary outcome measure is a composite of wound healing and freedom from amputation at 12&#xa0;months. Secondary outcome measures include technical success, amputation-free survival, changes in Rutherford category, limb perfusion and wound, ischemia, and foot infection (WIfI) score, patency, need for revascularization, safety, and patient-reported health-related quality of life (HRQoL). Results will be reported using mainly descriptive statistics. Patient enrollment opened in July 2024 and is planned to continue until July 2026, with the follow-up period expected to end in July 2028.</p> Conclusion <p>CALCIO intends to provide valuable insights into the real-world long-term clinical outcomes of IVL to support decision making regarding the optimal endovascular treatment for CLTI patients. CALCIO is registered on ClinicalTrials.gov (NCT06149650).</p> Graphical Abstract <p></p>