After unsatisfactory results in a first-in-human clinical investigation with an anatomically shaped medial meniscus prosthesis, the prosthesis and its fixation technique were altered. This interim analysis of a prospective single-arm clinical investigation aims to evaluate safety and clinical performance in a first-in-human study with the redesigned meniscus prosthesis system. Ten patients suffering from medial postmeniscectomy pain syndrome were treated with the meniscus prosthesis. Patient-reported outcome measures were obtained at baseline and at 6-week, 3-, 6-, and 12-month follow-up. Radiographs and magnetic resonance imaging scans were obtained to evaluate joint degeneration and prosthesis location. The device alterations resolved the issues occurring with the previous design, but four prostheses were explanted after fixation failure or subluxation of the prosthesis. Five out of six patients who reached 1-year follow-up reported a clinically significant improvement of the knee injury and osteoarthritis outcome score pain subscale. Imaging revealed no adverse effects on joint degeneration. The failure mechanisms that occurred with the previous design have been resolved, but the new fixation technique introduced new safety issues. Improvement of positioning and fixation techniques are considered essential future adaptations to reduce the risk of failure. The good clinical outcomes reported by the patients reaching 1-year follow-up indicate that the medial meniscus prosthesis is a potential solution for patients suffering from postmeniscectomy pain syndrome. Level II.