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. 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? 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%. We observed no difference in 2-year change scores (postoperative minus preoperative score) in KA versus MA patients for the OKS (mean 21, SD 8 versus 20, SD 8, least square means 1.0, 95% confidence interval [CI], −1.4 to 3.4, p = 0.4), WOMAC score (mean 38, SD 18 versus 35, SD 8, least square means 3, 95% CI, −3.2 to 8.9, p = 0.3), or Forgotten Joint score (28 SD 37 versus 28, SD 28, least square means 0.8, 95% CI, −9.1–10.7, p = 0.8). Postoperative hip-knee-ankle axis was not different between groups (mean KA 0.4° varus SD 3.5 versus MA 0.7° varus SD 2.0), but in the KA group, the tibial component was a mean 1.9° more varus than the MA group (95% CI, 0.8°−3.0°, p = 0.003) and the femoral component in 1.6° more valgus (95% CI, −2.5° to −0.7°, p = 0.003). Complication rates were not different between groups. We found no difference in 2-year patient-reported outcome scores in TKAs implanted using the KA versus an MA technique. The theoretical advantages of improved pain and function that form the basis of the design rationale of KA were not observed in this study. Currently, it is unknown whether the alterations in component alignment seen with KA will compromise long-term survivorship of TKA. In this study, we were unable to demonstrate an advantage to KA in terms of pain or function that would justify this risk. Level I, therapeutic study.