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Purpose: The benefit of drug-eluting stents (DES) versus drug-coated balloons (DCB) in coronary artery in-stent restenosis (ISR) for the prevention of target lesion revascularization (TLR), stent thrombosis, and mortality remains uncertain. Our aim was to synthesize the available evidence from randomized clinical trials (RCTs) and observational studies that directly compare second-generation drug-eluting stents (SG-DES) and DCB for the treatment of coronary ISR., Methods: Medline, Embase, and Cochrane Central were searched for RCTs or observational studies, published up to March 15, 2017. A random effects model meta-analysis investigating clinical and angiographic outcomes was conducted for RCTs and observational studies that compared SG-DES versus DCB for the treatment of ISR., Results: Ten studies and 2,173 patients were included in this meta-analysis. The two treatment strategies were proven equal with regards to TLR, myocardial infarction, stent thrombosis, and cardiac mortality in both randomized and observational studies. No difference was found among RCTs for all-cause mortality, while in observational studies, patients who were treated with SG-DES had a lower mortality compared to DCB (OR: 0.47; 95% CI: 0.27-0.83). In the pooled analysis also (RCTs and observational studies), SG-DES were associated with lower all-cause mortality compared to DCB. Patients treated with SG-DES were also superior in terms of minimal lumen diameter (standardized mean difference: 0.39; 95% CI: 0.12-0.66)., Conclusions: The two treatment strategies are equal for the treatment of ISR, while the difference in all-cause mortality might be potentially explained by baseline differences in the two groups among real-world studies., (© 2017 Wiley Periodicals, Inc.)