Purpose: According to OARSI guidelines, management of knee osteoarthritis consists of a combination of both non-pharmaceutical and pharmaceutical treatments, including knee braces. However, evidence is still inconclusive for the benefits of bracing in the treatment of knee osteoarthritis. The aim of this randomized open-label clinical trial was to compare the efficacy of the Rebel Reliever® knee brace in combination with usual care to that of usual care alone, after a 6-week treatment period. Methods: 67 patients with symptomatic medial knee osteoarthritis (Kellgren-Lawrence grade II-IV) were randomized into 2 groups: Brace group (brace + usual care) and Control group (usual care alone). Rebel Reliever® is a lightweight aluminum knee brace which applies corrective forces by a 3-point pressure system, gradually adjustable. Usual care consisted of analgesics and self exercises program. Primary endpoint was the global last-24 h knee pain (assessed via a 100-mm visual analogic scale [VAS]) after 6 weeks of treatment. Secondary endpoints included pain during motion (100-mm VAS), function (Lequesne index), clinical global improvement according to both patients and investigators, responder rate (OARSI-OMERACT criteria), as well as observance. Results: Study population consisted of 67 patients aged 65.7 ± 9.6 years, mainly women (65.7%). Of them, 32 were assigned to the Brace group and 35 to the Control group. At baseline, last 24h-pain was 63.8 ± 10.6 mm in the Brace group and 64.7 ± 13.5 mm in the Control group. Pain during motion was 73.4 ± 12.7 mm and 71.9 ± 13.8 mm in the Brace and Control groups, respectively. Function (Lequesne index) was 13.42 ± 3.74 in the Brace group and 12.63 ± 3.22 in the Control group. After 6 weeks, last 24h-pain decrease in the Brace group was statistically higher compared to the Control group (−41.35 ± 3.37 mm vs. −15.37 ± 3.23 mm; p < 0.0001). Similarly, decrease in pain in motion was significantly higher in the Brace group than in the Control group (−51.91 ± 3.49 mm vs. −19.91 ± 3.34 mm; p < 0.0001). Improvement of algofunctional Lequesne index score was also significantly higher in the Brace group (−5.8 vs. −2.3; p < 0.001). Clinical global improvement was more pronounced in the Brace group, with more patients feeling ‘better’ to ‘considerably improved’ in the Brace group compared to the Control group (86.2% vs. 3.1%) and with investigators reporting more patients ‘much’ to ‘very much’ improved in the Brace group than in the Control group (82.1% vs. 3.1%). Responder rate (OARSI-OMERACT criteria) was significantly higher in the Brace group (72.4% vs. 34.4%; p = 0,003). These observed differences were clinically relevant. Observance to the brace was excellent ( > 90% of the actual/theoretical wearing days). Conclusions: Superiority of Rebel Reliever® knee brace + usual care compared to usual care alone was demonstrated. Combining Rebel Reliever® knee brace with usual care is a powerful non pharmacological therapeutic strategy to handle medial knee osteoarthritis. NCT02021136.