To compare the safety and efficacy of drug-coated balloon (DCB) vs uncoated balloon angioplasty in the treatment of de novo and restenotic infrapopliteal lesions in patients with chronic limb-threatening ischemia (CLTI). The prospective, multicenter, randomized study AcoArt II-BTK study (ClinicalTrials.gov identifier NCT02137577) enrolled 120 patients who were randomly assigned to angioplasty with either a DCB (n=61; mean age 70.7±7.4 years; 36 men) or a conventional balloon catheter (n=59; mean age 70.8±9.0 years; 36 men). There were no significant differences observed in baseline clinical or target lesion characteristics between the groups. The target lesion length was 169.95±86.35 mm in the DCB group vs 179.93±80.16 mm in the control group, and approximately three-quarters of the lesions were chronic occlusions. Primary patency was assessed by angiography at 6 months, and mortality and clinically-driven target lesion revascularization (CD-TLR) were evaluated at 12 months. Primary patency at 6 months was 75.0% in the DCB group and 28.3% in the control group (p<0.001), while late lumen loss was 0.43±0.62 mm for DCBs vs 0.99±0.55 mm for controls (p<0.001). Freedom from CD-TLR at 12 months was 91.5% in the DCB group vs 76.8% in the controls (p=0.03); there was no significant difference in mortality (1.7% DCB vs 3.6% controls; p=0.53). This study demonstrated that the Litos/Tulip DCBs are safe and effective in treating infrapopliteal lesions, with improved angiographic and clinical outcomes vs plain balloon angioplasty. The DCBs demonstrated significantly higher primary patency with fewer CD-TLRs than conventional angioplasty. The safety of the DCBs was noninferior to that of the uncoated balloons after 1 year of follow-up.