To compare the efficacy of a 12-week non-surgical treatment program with usual care in patients with knee osteoarthritis (OA) not eligible for total knee replacement (TKR).This two-arm parallel group assessor-blinded randomized controlled trial (RCT) included 100 adults from secondary care with knee OA, confirmed by radiography (Kellgren-Lawrence grade ≥1), but not eligible for a TKR. The 12-week non-surgical treatment program consisted of individualized progressed neuromuscular exercise, patient education, insoles, dietary advice and prescription of pain medication if indicated, while usual care comprised two leaflets with information and advice on knee OA and recommended treatments. The primary outcome was the change from baseline to 12 months in the Knee injury and Osteoarthritis Outcome Score (KOOS)4 defined as the average score for the KOOS subscales of pain, symptoms, activities of daily living (ADL), and quality of life (QOL).91% of the patients completed the 12 months follow-up on the primary outcome. Compared with usual care, patients undergoing the treatment program improved more in KOOS4 (adjusted mean difference (95% CI) of 9.6 (4.4-14.8)) with no serious treatment-related adverse events (AE). The number needed to treat (NNT), defined as the number of patients needed to treat for one person to improve 15% was 7.2. Secondary outcomes supported the primary findings.In patients with mostly moderate to severe knee OA not eligible for TKR, a 12-week individualized, non-surgical treatment program is more efficacious at 12 months compared with usual care and has few treatment-related AE.ClinicalTrials.gov (NCT01535001).