Background: Radial access has been associated with many advantages in percutaneous coronary intervention compared with femoral access. However, many international registries have reported poor adherence to this technique. Objectives: The aim of this study was to evaluate the safety, efficacy and operational efficiency of percutaneous coronary intervention according to the access site and the clinical presentation of the patient. Methods: A single-center, retrospective registry of patients with coronary artery disease undergoing percutaneous coronary intervention was conducted from March 2009 to June 2018 according to the vascular access. A Cox proportional-hazards model was used to analyze the association between vascular access and risk of major cardiovascular events, and a logistic regression model was applied to assess the relationship between major bleeding and access site complications. Total hospital stay and total hospitalization costs were measured to evaluate the operational efficiency. Results: A total of 8,155 percutaneous coronary interventions (mean follow-up of 1,448.6±714.1 days), via radial access (n=5,706) or femoral access (n=2,449), were included in the study. At 30 days, the risk of major cardiovascular events was significantly lower with the radial access (HR 0.66 [0.5-0.88], p=0.004), at the expense of a reduction in all-cause mortality. In addition, radial access significantly reduced the risk of major bleeding (HR 0.33 [0.16-0.67], p=0.002) and access site complications (HR 0.72 [0.53-0.98], p=0.038). A significant interaction was observed between the vascular access site and the risk of events according to the clinical presentation on admission. Use of radial access was associated with a significant reduction in the length of total hospital stay (≈30%) and total hospitalization costs (≈15%). Conclusions: The use of radial access in percutaneous coronary intervention was safe and effective compared with the femoral access, with lower rates of major cardiovascular events at 30 days, lower risk of major bleeding and of access site complications. Moreover, radial access was associated with greater operational efficiency during hospitalization.