Drug-eluting stent (DES) in-stent restenosis (ISR) can be treated by restenting using the same DES as previously placed (same stent strategy), versus switching to a stent that elutes a different drug (different stent strategy). To compare the efficacy of these strategies, a meta-analysis of controlled trials and observational studies evaluating patients with DES ISR was performed. The primary outcome was target lesion revascularization or target vessel revascularization, and secondary outcomes were major adverse cardiovascular events, death, and myocardial infarction. Pooled odds ratios (ORs) were calculated with the generic inverse variance method using a random-effects model. The chi-square test was used to evaluate heterogeneity. Ten studies (1,680 patients) were included. There was no significant heterogeneity among the studies for any end point. The different stent strategy was found to reduce the odds of target lesion revascularization or target vessel revascularization (OR 0.73, 95% confidence interval [CI] 0.55 to 0.96) and major adverse cardiovascular events (OR 0.72, 95% CI 0.54 to 0.96). There was no difference between the 2 strategies in rates of death (OR 1.03, 95% CI 0.49 to 2.16) or myocardial infarction (OR 0.59, 95% CI 0.24 to 1.41). In conclusion, this study demonstrates that treatment of DES ISR by restenting with a different DES than previously placed may lead to improved outcomes compared with the use of the same DES. Further large-scale trials are needed to confirm this effect.