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Purpose: The aim of the study was to evaluate the long-term clinical results, reoperations, surgical failure and complications at a minimum of 20 year of follow-up of the first 8 medial CMI scaffolds implanted by a single surgeon during a pilot European Prospective study., Methods: Seven (88%) out of 8 patients were contacted. The Cincinnati Score, VAS, and Lysholm score were collected. Moreover, magnetic resonance imaging (MRI) was performed on 4 patients at the last follow-up. Complications, reoperations and failures were also investigated., Results: The average follow-up was 21.5 ± 0.5 years. One patient underwent TKA after 13 years from CMI implantation; a second patient underwent valgus high tibial osteotomy 8 years after the index surgery and another patient underwent anterior cruciate ligament hardware removal at 21 years of follow-up. At the final follow-up, 3 patients were rated as "Excellent", 1 as "Good" and 2 as "Fair" according to the Lysholm score. The Cincinnati score and the VAS were substantially stable over time. The MRI showed a mild osteoarthritis progression in 3 out of 4 patients according to the Yulish score, and the CMI signal was similar to the mid-term follow-up revealing 3 cases of myxoid degeneration and 1 case of normal signal with reduced scaffold size., Conclusion: The medial CMI is a safe procedure: satisfactory clinical results and a low failure rate could be expected even at a long-term follow-up. For this purpose, the correct indication as well as correcting axial malalignment and addressing knee instability at the time of the index surgery is mandatory. On the other hand, a mild osteoarthritis progression could be expected even after meniscus replacement., Level of Evidence: IV., (© 2021. The Author(s).)