Background: Lateral wedge insoles adjusted by biomechanical analysis may improve the condition of patients with medial knee osteoarthritis. Design: This is a prospective, randomized, controlled, single-blind clinical trial. Setting: The study was conducted in a biomechanics laboratory. Subjects: A total of 38 patients with medial knee osteoarthritis were allocated to either an experimental group (lateral wedge insoles) or a control group (neutral insoles). Interventions: Experimental group ( n = 20) received an adjusted lateral wedge insole of 2, 4, 6, 8, or 10 degrees, after previous biomechanical analysis. Control group ( n = 18) received a neutral insole (0 degrees). All patients used the insoles for 12 weeks. Main measures: Visual analogue scale, Knee Injury and Osteoarthritis Outcome Score questionnaire, biomechanical parameters: first and second peak of the external knee adduction moment and knee adduction angular impulse, and physical performance tests: 30-second sit-to-stand test, the 40-m fast-paced walk test, and the 12-step stair-climb test. Results: After 12 weeks, between-group differences did not differ significantly for pain intensity (−12.5 mm, (95% CI −29.4–4.4)), biomechanical parameters ( p = 0.05), Knee Injury and Osteoarthritis Outcome Score, and physical performance tests, except on the Knee Injury and Osteoarthritis Outcome Score subscale other symptoms ( p = 0.002; 13.8 points, (95% CI 5.6–22.0)). Conclusion: Tailored wedge insoles were no more effective at improving biomechanical or clinically meaningful outcomes than neutral insoles, except on symptoms. More participants from the experimental group reported they felt some improvement. However, these effects were minimal and without clinical significance.