In an effort to minimize periprocedural stroke risk, increasingly, electrophysiological (EP) procedures are being performed on anticoagulation. The decrease in stroke has been accompanied by an increase in potentially devastating vascular access complications. Ultrasound guidance for femoral vein cannulation reduces complications in other applications. The aim of this study is to determine the utility of real-time two-dimensional (2D) ultrasound guidance for femoral vein cannulation in EP. A comprehensive literature search of Medline, Embase, Google Scholar, and the Cochrane Central Register of Controlled Trials was performed. Five years of conference abstracts from the Heart Rhythm Society, European Heart Rhythm Association, and European Cardiac Arrhythmia Society were reviewed. Two independent reviewers identified trials comparing ultrasound-guided with standard cannulation in EP procedures. Data were extracted on study design, study size, operator and patient characteristics, use of anticoagulation, vascular complication rates, first-pass success rate, and inadvertent arterial puncture. Four trials, with a total of 4065 subjects, were included in the review, with 1848 subjects in the ultrasound group and 2217 subjects in the palpation group. Ultrasound guidance for femoral vein cannulation was associated with a 60% reduction of major vascular bleeding (relative risk, 0.40; 95% confidence interval, 0.28-0.91). Additionally, there was a 66% reduction in minor vascular complications (relative risk, 0.34; 95% confidence interval, 0.15-0.78). The use of real-time 2D ultrasound guidance for femoral vein cannulation decreases access-related bleeding rates and life-threatening vascular complications.