The purpose of this study was to compare 2 alignment methods for total knee arthroplasty (TKA): kinematic alignment with the use of patient-specific guides and mechanical alignment with conventional ...instruments. A randomized, controlled trial of 41 kinematically aligned and 41 mechanically aligned patients was conducted with the patient, radiographic evaluator, and clinical evaluator blinded to the alignment technique. Radiographic measurements were made from long-leg computer tomography scanograms. Clinical outcome scores and motion were measured preoperatively and 6 months postoperatively. The hip-knee-ankle angle (0.3° difference; P=.693) and anatomic angle of the knee (0.8° difference; P=.131) were similar for both groups. In the kinematically aligned group, the angle of the femoral component was 2.4° more valgus (P<.000) and the angle of the tibial component was 2.3° more varus (P<.000) than the mechanically aligned group. At 6 months postoperatively, the Western Ontario and McMaster Universities Osteoarthritis Index score was 16 points better (P<.000), Oxford Score was 7 points better (P=.001), combined Knee Society Score was 25 points better (P=.001), and flexion was 5.0° greater (P=.043) in the kinematically aligned group than in the mechanically aligned group.Our findings suggest that the risk of early failure related to limb or knee alignment should be similar in kinematic and mechanically aligned TKA. More anatomic alignment of the implant was associated with better flexion and better clinical outcome scores in the kinematically aligned group.