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Several biomechanics treatments for knee osteoarthritis (OA) have emerged with the goal of reducing pain and improving function. Through this, researchers have hoped to achieve a transition from the pathological gait patterns to coordinated motor responses. The purpose of the study was to determine the long-term effects of a therapy using a biomechanical device in patients with knee OA. Patients with knee OA were enrolled to active and control groups. The biomechanical device used in therapy (AposTherapy) was individually calibrated to each patient in the active group. Patients in the control group received standard treatment. Outcomes were the Western Ontario and McMaster Osteoarthritis Index (WOMAC), Aggregated Locomotor Function (ALF), Short Form 36 (SF-36), and Knee Society Score assessments. The active and control groups were similar at the baseline (group difference in all scores P > 0.05). The active group showed a larger improvement over time between groups in all three WOMAC categories (F = 16.8, 21.7, and 18.1 for pain, stiffness, and function; all P < 0.001), SF-36 Physical Scale (F = 5.8; P = 0.02), Knee Society Knee Score (F = 4.3; P = 0.044 ), and Knee Society Function Score (F = 6.5; P = 0.014 ). At the two-year endpoint, the active group showed significantly better results (all P ≤ 0.001). The groups showed a difference of 4.9, 5.6, and 4.7 for the WOMAC pain, stiffness, and function scores, respectively, 10.8 s in ALF score, 30.5 in SF-36 Physical Scale, 16.9 in SF-36 Mental Scale, 17.8 in Knee Society Knee Score, and 25.2 in Knee Society Function Score. The biomechanical therapy examined was shown to significantly reduce pain and improve function and quality of life of patients with knee OA over the long term.