The impact of endoscopic retrograde cholangiopancreatography (ERCP) mechanical simulator (EMS) practice on trainee clinical performance is unknown. The hypothesis that trainees with EMS practice (study group (SG)) have improved clinical outcomes compared with those without such practice (control group (CG)) is tested. This was a randomized controlled trial involving six US academic centers. Sixteen trainees were randomized after ERCP didactic teaching. SG (n=8) participated in two sessions of EMS practice on selective cannulation; CG (n=8) did not undergo EMS practice. All participants' clinical performances were monitored in the subsequent 16 weeks. Intervention effects were assessed in multivariable regression models using generalizing estimating equations (GEE) to account for cluster randomization of trainees. The primary outcome was successful biliary cannulation, and secondary outcomes were cannulation time and competency score. Cannulation success rate was 47.1% for CG and 69.6% for SG. SG had higher odds of successful cannulation (adjusted odds ratio=3.01, P=0.021). SG trainees achieved faster cannulation time (min) (4.7±4.2 vs. 10.3±14.1, P<0.001). Trainee competency scores given by supervising physicians were comparable confirming adequate blinding of the trainers. Limitations included short observation period, small number of ERCPs performed by individual trainees, and variation in the number of ERCPs between trainees. In a prospective multicenter randomized controlled trial during early training, a significantly higher proportion of the biliary cannulations performed by trainees with EMS practice were successful and with faster cannulation time compared with those performed by trainees without such practice. The results provide objective evidence to support the continued evaluation of EMS practice to augment clinical training.