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Objectives: The safest site for central venous cannulation (CVC) remains debated. Many emergency physicians (EPs) advocate the ultrasound-guided internal jugular (USIJ) approach because of data supporting its efficiency. However, a number of physicians prefer, and are most comfortable with, the subclavian (SC) vein approach. The purpose of this study was to describe adverse event rates among operators using the USIJ approach, and the landmark SC vein approach without US. Methods: This was a prospective observational trial of patients undergoing CVC of the SC or internal jugular veins in the emergency department (ED). Physicians performing the procedures did not undergo standardized training in either technique. The primary outcome was a composite of adverse events defined as hematoma, arterial cannulation, pneumothorax, and failure to cannulate. Physicians recorded the anatomical site of cannulation, US assistance, indications, and acute complications. Variables of interest were collected from the pharmacy and ED record. Physician experience was based on a self-reported survey. The authors followed outcomes of central line insertion until device removal or patient discharge. Results: Physicians attempted 236 USIJ and 132 SC cannulations on 333 patients. The overall adverse event rate was 22% with failure to cannulate being the most common. Adverse events occurred in 19% of USIJ attempts, compared to 29% of non–US-guided SC attempts. Among highly experienced operators, CVCs placed at the SC site resulted in more adverse events than those performed using USIJ (relative risk [RR] = 1.89, 95% confidence interval [CI] = 1.05 to 3.39). Conclusions: While limited by observational design, our results suggest that the USIJ technique may result in fewer adverse events compared to the landmark SC approach. ACADEMIC EMERGENCY MEDICINE 2010; 17:416–422 © 2010 by the Society for Academic Emergency Medicine