IMPORTANCE: Individually calibrated biomechanical footwear therapy may improve pain and physical function in people with symptomatic knee osteoarthritis, but the benefits of this therapy are unclear. OBJECTIVE: To assess the effect of a biomechanical footwear therapy vs control footwear over 24 weeks of follow-up. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at a Swiss university hospital. Participants (N = 220) with symptomatic, radiologically confirmed knee osteoarthritis were recruited between April 20, 2015, and January 10, 2017. The last participant visit occurred on August 15, 2017. INTERVENTIONS: Participants were randomized to biomechanical footwear involving shoes with individually adjustable external convex pods attached to the outsole (n = 111) or to control footwear (n = 109) that had visible outsole pods that were not adjustable and did not create a convex walking surface. MAIN OUTCOMES AND MEASURES: The primary outcome was knee pain at 24 weeks of follow-up assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore standardized to range from 0 (no symptoms) to 10 (extreme symptoms). The secondary outcomes included WOMAC physical function and stiffness subscores and the WOMAC global score, all ranging from 0 (no symptoms) to 10 (extreme symptoms) at 24 weeks of follow-up, and serious adverse events. RESULTS: Among the 220 randomized participants (mean age, 65.2 years SD, 9.3 years; 104 women 47.3%), 219 received the allocated treatment and 213 (96.8%) completed follow-up. At 24 weeks of follow-up, the mean standardized WOMAC pain subscore improved from 4.3 to 1.3 in the biomechanical footwear group and from 4.0 to 2.6 in the control footwear group (between-group difference in scores at 24 weeks of follow-up, −1.3 95% CI, −1.8 to −0.9; P < .001). The results were consistent for WOMAC physical function subscore (between-group difference, −1.1 95% CI, −1.5 to −0.7), WOMAC stiffness subscore (between-group difference, −1.4 95% CI, −1.9 to −0.9), and WOMAC global score (between-group difference, −1.2 95% CI, −1.6 to −0.8) at 24 weeks of follow-up. Three serious adverse events occurred in the biomechanical footwear group compared with 9 in the control footwear group (2.7% vs 8.3%, respectively); none were related to treatment. CONCLUSIONS AND RELEVANCE: Among participants with knee pain from osteoarthritis, use of biomechanical footwear compared with control footwear resulted in an improvement in pain at 24 weeks of follow-up that was statistically significant but of uncertain clinical importance. Further research would be needed to assess long-term efficacy and safety, as well as replication, before reaching conclusions about the clinical value of this device. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02363712