The frequency and outcomes of patients who underwent chronic total occlusion (CTO) percutaneous coronary intervention (PCI) of more than one CTO during the same procedure have received limited study. We compared the clinical and angiographic characteristics and procedural outcomes of patients who underwent treatment of single versus >1 CTOs during the same procedure in 20 centers from the United States, Europe, and Russia. A total of 2,955 patients were included: mean age was 65 ± 10 years and 85% were men with high prevalence of previous myocardial infarction (46%), and previous coronary artery bypass graft surgery (33%). More than one CTO lesions were attempted during the same procedure in 58 patients (2.0%) and 70% of them were located in different major epicardial arteries. Compared with patients who underwent PCI of a single CTO, those who underwent PCI of >1 CTOs during the same procedure had similar J-CTO (2.4 ± 1.3 vs 2.5 ± 1.3, p = 0.579) and Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (1.5 ± 1.2 vs 1.3 ± 1.0 p = 0.147) scores. The multi-CTO PCI group had similar technical success (86% vs 87%, p = 0.633), but higher risk of in-hospital major complications (10.3% vs 2.7%, p = 0.005), and consequently numerically lower procedural success (79% vs 85%, p = 0.197). The multi-CTO PCI group had higher in-hospital mortality (5.2% vs 0.5%, p = 0.005) and stroke (5.2%vs 0.2%, p <0.001), longer procedure duration (162 [117 to 242] vs 122 [80 to 186] minutes, p <0.001) and higher radiation dose (3.6 [2.1 to 6.4] vs 2.9 [1.7 to 4.7] Gray, p = 0.033). In conclusion, staged revascularization may be the preferred approach in patients with >1 CTO lesions requiring revascularization, as treatment during a single procedure was associated with higher risk for periprocedural complications.