The anteromedial (AMP) portal technique was introduced to position the femoral tunnel in anterior cruciate ligament (ACL) reconstruction to more closely replicate the original ACL footprint compared to the transtibial (TT) approach. Few randomized trials have evaluated differences in these techniques with respect to clinical outcomes. The purpose of this study was to determine if there are any differences in clinical outcome between the AMP and TT approaches. This is a single-blinded, prospective, randomized controlled trial. Participants were randomized to undergo ACL reconstruction using the AMP or TT approach. The primary outcome measure was the ACL quality of life (ACL-QOL), and secondary outcomes were the IKDC knee assessment, side-to-side difference in anterior-posterior knee laxity (KT-1000) and tunnel orientation (X-ray findings) at preoperative, 3, 6, 12, and 24months postoperative. Statistical comparisons were performed using a series of t tests for independent groups with equal variance. Ninety-six participants were consented and randomized between 2007 and 2011 with eight excluded postrandomization. Mean (SD) preoperative ACL-QOL was 33 (13) for TT and 36 (17) for AMP and improved significantly (p<0.001) in both groups to 79 (18) and 78 (18) at 24months postoperative, respectively. The preoperative median IKDC grade for both groups was C and improved similarly in both groups at 24months (n.s.). There was no side-to-side difference in knee laxity based on KT-1000 measurements with a mean (SD) 1 (3) mm between affected and unaffected limbs in the TT group compared to 1 (3) mm for the AMP group. A significant difference was found in femoral tunnel orientation with the AMP group at 43° (7) and the TT group 58° (8) in the coronal plane (p<0.001). No differences in clinical outcome were found when comparing AMP to TT in primary ACL reconstruction using a STG graft. This prospective randomized controlled trial suggests surgeons can use either method without significantly compromising clinical outcome. I.