The aim of this article is to systematically review the literature on medical adjunctive therapy for patients with chronic limbthreatening ischemia (ClTi). evidenCe aCQuisiTion: Medline, embase, and Cochrane database of systematic reviews were searched for studies published between January 1 st , 2009, and June 1 st , 2019. articles that studied medical treatment of ClTi patients and reported clinical outcomes were eligible. Main exclusion criteria were case reports <20 patients, incorrect publication type, and ClTi caused by Buerger disease. The primary end point was major amputation (above the ankle) in studies with a follow-up of ≥6 months. Secondary end points were other clinical end points such as death and wound healing. study quality was assessed according to the downs and Black checklist. EVIDENCE SYNTHESIS: Included were 42 articles: four focused on antiplatelet therapy, five on antihypertensive medication, 6 on lipid-lowering therapy, 16 on stem cell therapy, three on growth factors, five on prostanoids, and one study each on cilostazol, glucose-lowering therapy, spinal cord stimulation, sulodexide, and hemodilution. Calcium channel blockers, iloprost, cilostazol, and hemodilution showed significant improvement of limb salvage, but data are limited. Stem cell therapy showed no significant improvement of limb salvage but could potentially improve wound healing. Antiplatelets, antihypertensives, and statins showed significantly lower cardiovascular events rates but not evident lower major amputation rates. The quality of the studies was fair to good. ConClusions: Certain medical therapies serve to improve limb salvage next to revascularization in ClTi patients, whereas others are important in secondary prevention. Because high quality evidence is limited, further research is needed.