PurposeThe aim of this study was to prospectively evaluate the long‐term clinical results and failure rate of patients treated with complex salvage procedures using a combined mechanical and biological approach to address unicompartmental knee osteoarthritis (OA) and postpone the need for joint replacement.MethodsThirty‐nine patients (40.3 ± 10.9 years old) affected by unicompartmental OA (Kellgren–Lawrence 3) in stable joints underwent a personalized surgical treatment depending on the specific requirements of the affected compartment, including high tibial osteotomy, osteochondral scaffold, meniscal scaffold and meniscal allograft transplantation. Patients were evaluated with the International Knee Documentation Committee (IKDC), Visual Analogue Scale (VAS) and Tegner scores before surgery, at 3 years and a minimum of 10 years of follow‐up.ResultsA significant improvement was observed over time in all scores but worsened at the final follow‐up. The IKDC subjective score improved from 46.9 ± 16.2 to 79.8 ± 16.4 at 3 years (p < 0.0005) and then decreased to 64.5 ± 21.4 (p = 0.001) at 12 years. A similar trend was confirmed for VAS and Tegner scores. Only two patients subsequently underwent knee arthroplasty, and nine more patients were considered clinical failure, for a cumulative surgical and clinical failure rate of 28.2% at the final follow‐up.ConclusionA personalized, joint‐preserving, combined mechanical and biological approach, addressing alignment as well as meniscal and cartilage lesions, is safe and effective, providing a clinical benefit and delaying the need for arthroplasty in young patients affected by unicompartmental knee OA. At the final evaluation, the clinical improvement decreased, but more than two‐thirds of the patients still benefited from this treatment at a long‐term follow‐up.Level of EvidenceLevel IV case series.