Background Neutral mechanical alignment (MA) in total knee arthroplasty (TKA) aims to position femoral and tibial components perpendicular to the mechanical axis of the limb. In contrast, kinematic alignment (KA) attempts to match implant position to the prearthritic anatomy of the individual patient with the aim of improving functional outcome. However, comparative data between the two techniques are lacking.Questions/purposes In this randomized trial, we asked: (1) Are 2-year patient-reported outcome scores enhanced in patients with KA compared with an MA technique? (2) How does postoperative component alignment differ between the techniques? (3) Is the proportion of patients undergoing reoperation at 2 years different between the techniques? Methods Ninety-nine primary TKAs in 95 patients were randomized to either MA (n = 50) or KA (n = 49) groups. A pilot study of 20 TKAs was performed before this trial using the same patient-specific guides positioning in kinematic alignment. In the KA group, patient-specific cutting blocks were manufactured using individual preoperative MRI data. In the MA group, computer navigation was used to ensure neutral mechanical alignment accuracy. Postoperative alignment was assessed with CT scan, and functional scores (including the Oxford Knee Score, WOMAC, and the Forgotten Joint Score) were assessed preoperatively and at 6 weeks, 6 months, and 1 and 2 years postoperatively. No patients were lost to followup. We set sample size at a minimum of 45 patients per treatment arm based on a 5-point improvement in the mean Oxford Knee Score (OKS; the previously reported minimum clinically significant difference for the OKS in TKA), a pooled SD of 8.3, 80% power, and a two-sided significance level of 5%. Results We observed no difference in 2-year change scores (postoperative minus preoperative score) in KA versus MA The institution of one or more of the authors (SWY, MLW, AB, BF) has received, during the study period, funding from Stryker (Kalamazoo, MI, USA) One or more of the authors (AB, MLW, BF) or a member of his or her immediate family, has or may receive payments or benefits, during the study period, an amount of less than USD 10,000 from Stryker. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research 1 editors and board members are on file with the publication and can be viewed on request. Clinical Orthopaedics and Related Research 1 neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDAapproval status, of any drug or device prior to clinical use. Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained. This work was performed at the Department of Orthopaedics, North Shore Hospital, Auckland, New Zealand. Postoperative hipknee-ankle a...