PURPOSE: Drug-coated balloon angioplasty (DCBA) has been studied as a potentially superior option compared to conventional percutaneous transluminal angioplasty (PTA) in treating below-the-knee (BTK) arteries in chronic limb-threatening ischemia (CLTI). The aim of this study is to examine the cost-effectiveness of DCBA versus PTA in BTK arteries based on a randomized controlled trial. MATERIAL AND METHODS: A prospective economic study was embedded in a randomized controlled trial of 138 patients with CLTI. Resource use and health outcomes were assessed at baseline, and at 3, 6 and 12 months post-intervention. Costs were calculated from a societal perspective and health outcomes measured using quality-adjusted life years with probabilistic sensitivity analysis performed to account for subject heterogeneity. RESULTS: Compared with participants randomized to receive PTA, participants randomized to DCBA gained an average baseline-adjusted quality-adjusted life years (QALYs) of .012 while average total costs were USD$1854 higher; this translates to an incremental cost-effectiveness ratio (ICER) of US$154,500 additional cost per QALY gained. However, the estimate of ICER had substantial variance with only 48% of bootstrap ICERs meeting a benchmark threshold of US$57,705 (the average gross domestic product (GDP) per capita of Singapore). CONCLUSION: The use of DCBA in BTK arteries in CLTI patients was not cost-effective compared with PTA. LEVEL OF EVIDENCE: 2, Randomized trial.