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Background: The usefulness of drug-eluting balloons (DEBs) has not been fully elucidated in calcified coronary lesions (CCLs). This meta-analysis aimed to evaluate the efficacy of DEBs compared to a drug-eluting stent (DES) in this setting. Methods: PubMed, EMBASE and Cochrane were searched through December 2023. The primary endpoint was 12 months major adverse cardiac events (MACE). Secondary endpoints included clinical outcomes and angiographic results after PCI and at a 12-month follow-up. Results: Five studies and a total of 1141 patients with 1176 coronary lesions were included. Overall, the DEB was comparable to DES in MACE (RR = 0.86, 95% CI: 0.62–1.19, p = 0.36), cardiac death (RR = 0.59, 95% CI: 0.23–1.53, p = 0.28), myocardial infarction (RR = 0.89, 95% CI: 0.25–3.24, p = 0.87) and target lesion revascularization (RR = 1.1, 95% CI: 0.68–1.77, p = 0.70). Although the DEB was associated with worse acute angiographic outcomes (acute gain; MD = −0.65, 95% CI: −0.73, −0.56 and minimal lumen diameter; MD = −0.75, 95% CI: −0.89, −0.61), it showed better results at 12 months follow-up (late lumen loss; MD = −0.34, 95% CI: −0.62, −0.07). Conclusions: This meta-analysis showed that the DEB strategy is comparable to DES in the treatment of CCLs in terms of clinical outcomes. Although the DEB strategy had inferior acute angiographic results, it may offer better angiographic results at follow-up. [ABSTRACT FROM AUTHOR]