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Objective To compare vascular complications in patients undergoing percutaneous coronary intervention (PCI) of chronic total occlusions (CTO) using ultrasound guidance (USG) versus fluoroscopy guidance (FSG) for femoral access. Background In patients undergoing PCI, using the arterial femoral access increases the risk of vascular complications compared using the radial access. USG reduces time to access, number of attempts, and vascular complications compared with FSG, but the efficacy of USG has never been tested in the setting of CTO-PCI. Methods A total of 197 patients undergoing CTO-PCI using at least a femoral vascular access from November 2015 to September 2020 were screened. The primary outcome was a composite of local hematoma, pseudoaneurysm , retroperitoneal hemorrhage , arteriovenous fistula or hemoglobin drop ≥3 g/dL during hospitalization. The independent association between USG and the primary outcome of interest was explored. Results The primary outcome occurred in 17.3% of patients. Patients in the USG group had a significantly lower incidence of vascular complications compared with patients in the FSG group (8.5% vs. 21.0%, p = 0.039), driven by a reduction of localized hematomas (3.4% vs 13.0%, p = 0.042). After adjustment for type of CTO approach and heparin dose, USG was significantly associated with a reduced relative risk of the composite primary outcome (adjusted odds ratio 0.16, 95% confidence interval 0.05 to 0.51; p = 0.002). Conclusion USG in CTO-PCI is associated with a decreased risk of vascular complications, primarily driven by a reduction in local hematomas, especially in complex CTO-PCI where the larger use of heparin increases the risk of vascular complications.