BackgroundIn-stent restenosis (ISR) chronic total occlusion (CTO) represents a challenging subgroup for revascularization of CTO by percutaneous coronary intervention (PCI). There are limited data on the treatment and outcomes of PCI for ISR CTO.ObjectiveWe aimed to evaluate the procedural results and 2-year outcomes of PCI for ISR CTO compared with de novo CTO.MethodsPatients undergoing attempted CTO PCI between January 2017 and December 2019 were prospectively enrolled. We analyzed the procedural results and 2-year major adverse cardiac events (MACE) in patients undergoing ISR CTO and those undergoing de novo CTO PCI.ResultsA total of 426 patients undergoing 484 consecutive CTO PCI (ISR CTO PCI, n=84; de novo CTO, n=400) were enrolled during the study period. Patients undergoing de novo CTO PCI had a significantly greater syntax score than those undergoing ISR CTO PCI [23.0 (17.5, 30.5) vs 21.5 (14.5, 27.0), p=0.039]. Technical (73.8% vs 79.0%, p=0.296) and procedural (73.8% vs 78.0, p=0.405) success rates, as well as the incidence of major procedural complications (1.2% vs 2.3%, p=0.842), were comparable between the two groups. After a median follow-up of 20 months, patients who underwent ISR CTO PCI had a significantly higher incidence of MACE (33.3% vs 10.3%, p<0.001), mainly attributed to the higher TVR rates (24.7% vs 7.6%, p<0.001). ISR CTO was the only independent predictor of MACE (hazard ratio, 4.124; 95% confidence interval, 1.951–8.717; p<0.001) during follow-up in patients who underwent CTO PCI.ConclusionISR CTO PCI shows comparable technical and procedural success, as well as major procedural complications compared with de novo CTO PCI. However, patients who underwent ISR CTO PCI had a significantly worse prognosis than those who underwent de novo CTO PCI, in terms of MACE, driven by TVR. ISR CTO was the only independent predictor of MACE during the follow-up.