Background: Drug-coated balloons have been used as a non-stenting treatment in coronary and peripheral artery disease. Until recently, only sirolimus- and paclitaxel-coated balloons have been investigated in clinical trials. We evaluated the safety and efficacy of an innovative everolimus-coated balloon (ECB) in a swine coronary artery model. Methods: thirty-two swine coronary arteries were prepared through dilatation with a non-coated angioplasty balloon in a closed-chest model. During a period of 90 days, the following four groups (four animals per group, two coronary arteries per animal) were compared for safety and efficacy: A, Rontis ECB with 2.5 μg/mm2 of drug per balloon surface; B, Rontis ECB with 7.5 μg/mm2; C, Rontis Europa Ultra bare balloon; and D, Magic Touch, Concept Medical, sirolimus-coated balloon with a drug load of 1.3 μg/mm2. Results: Differences in local biological effects (arterial reaction scores) and surface of intimal area (mm2) were not statistically significant between the treatment groups. Numerically, group A showed the lowest intimal area and intimal mean thickness, while group B showed the lowest stenosis among all groups. Conclusions: ECB was safe and effective in a porcine coronary artery model. The dose of everolimus may play a role in the biocompatibility of the balloon.