Background Ultrasound ( US ) guidance provides the unique opportunity to control the puncture zone of the artery during transfemoral transcatheter aortic valve replacement and may decrease major vascular complications ( VC ) and life‐threatening or major bleeding complications. This study aimed to evaluate the clinical impact of US guidance using a propensity score–matched comparison. Methods and Results US guidance was implemented as the default approach for all transfemoral transcatheter aortic valve replacement cases in our institution in June 2013. We defined 3 groups of consecutive patients according to the method of puncture (fluoroscopic/ US guidance) and the use of a transcatheter heart valve. Patients in the US ‐guided second‐generation group (Sapien XT [Edwards Lifesciences, Irvine, CA], Corevalve [Medtronic, Dublin, Ireland]) were successfully 1:1 matched with patients in the fluoroscope‐guided second‐generation group (n=95) with propensity score matching. In a second analysis we described the consecutive patients of the US ‐guided third‐generation group (Evolut‐R [Medtronic], Sapien 3 [Edwards Lifesciences], n=308). All vascular and bleeding complications were reduced in the US ‐guided second‐generation group compared with the fluoroscope‐guided second‐generation group: VC (16.8% versus 6.3%; P =0.023); life‐threatening or major bleeding (22.1% versus 6%; P =0.004); and VC related to vascular access (12.6% versus 4.2%; P =0.052). In the US ‐guided third‐generation group the rates of major VC and life‐threatening or major bleeding were 3.2% (95% CI , 1.6% to 5.9%) and 3.6% (95% CI , 1.8% to 6.3%). In the overall population (n=546), life‐threatening or major bleeding was associated with a 1.7‐fold increased mortality risk ( P =0.02). Conclusions We demonstrated that US guidance effectively reduced VC and bleeding complications for transfemoral transcatheter aortic valve replacement and should be considered the standard puncture method. Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02628509.