We aimed to investigate the safety of drug-coated balloon (DCB)-only percutaneous coronary intervention compared to drug-eluting stent (DES) for de novo lesions in large vessels. To pursue this goal, we conducted a systematic review and meta-analysis following the PRISMA guidelines. The analysis included studies that utilized DCB-only or hybrid angioplasty for de novo lesions in large coronary vessel (>
2.75 mm). The primary outcome was to assess the target lesion revascularization (TLR) rate, while secondary outcomes included cardiac death, myocardial infarction (MI), and the composite of these. A total of 15 studies, comprising 3975 patients (of whom 2114 treated with DCB) were included. Median age was 62 ± 1.5 years, with 77.4% being male. Overall, 26.9% had diabetes, and 67.6% were diagnosed with acute coronary syndrome. Over a pooled follow-up of 20.6 ± 1.9 months, the incidence of TLR was 4% in the pooled DBC group. Additionally, over a pooled follow-up of 25.8 ± 2.7 months, no significant differences were observed in incidence of TLR between the DCB group and the DES group (4.3% vs. 6.9%, odds ratio 0.71, 95% confidence interval 0.50-1.01, p = 0.059). Furthermore, there were no differences in incidence of cardiac death and MI. DCB angioplasty treatment of de novo lesions in large coronary vessels could be a safe and effective strategy in both acute and chronic coronary settings. The incidence of target lesion revascularization appears to be similar to that of contemporary DES.