OBJECTIVES The aim of this study was to investigate the outcomes of patients with de novo lesions in small coronary vessels undergoing percutaneous coronary intervention (PCI) with drug-coated balloons (DCBs) or newer-generation drug-eluting stents (n-DES). BACKGROUND Notwithstanding the available evidence from a few randomized clinical trials and meta-analyses, the best device for PCI in patients with small-vessel coronary artery disease is not yet established. METHODS The study included all consecutive patients with de novo lesions in small coronary vessels undergoing PCI in Sweden from April 2009 to July 2017. A small coronary vessel was defined by a device diameter <= 2.5 mm. The primary outcomes were restenosis and definite target lesion thrombosis at 3-year follow-up. The secondary outcomes were the occurrence of all-cause death and myocardial infarction. RESULTS The study population included 14,788 patients: 1,154 treated with DCBs and 13,634 with n-DES. Overall, 35,541 PCIs were performed using 2,503 DCBs and 33,038 n-DES. The propensity score-adjusted regression analysis showed a significantly higher risk for restenosis in the DCB group compared with the n-DES group (adjusted hazard ratio [HR]: 2.027; 95% confidence interval [CI]: 1.537 to 2.674). Conversely, no difference in the risk for target lesion thrombosis (adjusted HR: 0.741; 95% CI: 0.412 to 1.331) was detected. The risk for all-cause death (adjusted HR: 1.178; 95% CI: 0.992 to 1.399) and myocardial infarction (adjusted HR: 1.251; 95% CI: 0.960 to 1.629) was comparable between groups. CONCLUSIONS Because of the significantly higher risk for restenosis up to 3 years, this research suggests that DCBs are not an equally effective alternative to n-DES for percutaneous treatment of small coronary vessels. (C) 2020 by the American College of Cardiology Foundation.