Background: Proximal vessel tortuosity can hinder wiring and equipment delivery during chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Aims: We sought to examine the association of proximal vessel tortuosity with the short and long-term outcomes of patients undergoing CTO PCI. Methods: We examined the association of proximal vessel tortuosity with clinical outcomes in patients who underwent CTO PCI at 50 US and non-US centers between 2012 and 2024. Results: Of 14,141 patients, 3,974 (28.1%) had moderate or severe proximal vessel tortuosity. Patients with moderate or severe proximal vessel tortuosity had more comorbidities and more complex angiographic characteristics, such as longer lesion length and higher prevalence of side branch at the proximal cap. Lesions with moderate or severe proximal tortuosity required greater procedure and fluoroscopy time. On unadjusted analyses, moderate/severe proximal vessel tortuosity was associated with lower technical success and higher incidence of major adverse cardiac events (MACE). In multivariable analysis, moderate/severe proximal vessel tortuosity was associated with lower technical success (odds ratio [OR]: 0.77; 95% confidence intervals [CI]: 0.67, 0.89) but similar MACE (OR: 1.26; 95% CI: 0.91, 1.73). Higher operator volume (≥ 30 CTO PCI cases per year) was associated with higher technical (85.2% vs. 75.6%, p < 0.001) and procedural success (83.6% vs. 74.5%, p < 0.001) but also higher risk of perforation (6.49% vs. 3.57%, p < 0.001) but not pericardiocentesis, in lesions with moderate/severe proximal vessel tortuosity. Conclusions: Moderate or severe proximal vessel tortuosity is independently associated with lower technical success in CTO PCI but not with MACE. High-volume operators are more likely to successfully perform CTO PCI in lesions with moderate/severe tortuosity at the cost of higher risk of perforation, without higher MACE.