Knee pain is one of the most common lower leg complaints. It is often treated with plantar orthoses to provide cushioning and correct locomotion, imbalances of the foot, and postural deficits. However, the published scientific data are poor concerning the mechanisms involved in pain reduction after wearing foot orthoses, and, to the best of our knowledge, no trial has investigated the mid-term effectiveness. The aim of the present study was to evaluate the effectiveness of foot orthoses according to sound biomechanical principles in the treatment of knee pain. Attention was mainly focused on changes in the central control strategies. Fifteen subjects were included in the protocol. The patients with knee pain were compared with healthy participants (control group) exhibiting no knee pain. In the patients with knee pain, pain perception, dynamic analysis of the gait, stabilometry, the soleus Hoffmann reflex at rest and during voluntary contraction, and V-wave were measured before and 3, 6, and 9 weeks after wearing orthoses. In the control group (n = 5), the same parameters were recorded at 0, 3, 6, and 9 weeks, but the subjects had not worn orthoses. In the patient group (n = 10), the results indicated that pain had significantly decreased from the third week onward, although the parameters of gait and stabilometry remained unchanged. From the sixth week, the soleus Hoffmann reflex during voluntary contraction wave was significantly reduced, suggesting an increase in motoneuronal presynaptic inhibition by non-nociceptive afferents. The V-wave amplitude increased throughout the 9 weeks of the experiment, suggesting a progressive increase in corticospinal and/or extrapyramidal descending pathway inputs, probably due to pain reduction. In the control group, no change was observed throughout the experimental sessions. Our data indicated that foot orthoses relieved patients' knee pain and reduced the descending motor inhibition. Changes in spinal modulation could contribute to a better quality of life. However, this treatment failed to change the altered gait, despite changes in spinal and supraspinal modulation. (C) 2017 by the American College of Foot and Ankle Surgeons. All rights reserved.