Objective: Meniscus regeneration is limited, moreover, loss of meniscal tissue leads to osteoarthritis. A new biomaterial, consisting of hyaluronic acid and polycaprolactone was applied as a meniscus substitute device in a study in sheep. Methods: 24 sheep received a total medial meniscal replacement. Group SCF (n=12) was treated with a cell free scaffold, Group SCS (n=12) with a scaffold seeded with autologous chondrocytes harvested from the contralateral joints, which served as sham controls (n=12). Further 12 non-operated and 2 menisectomy controls were included in the study. The animals were sacrificed after 4 months. The implants and joint surfaces were evaluated on a macroscopic (Implant Gross Assessment Score; Gross Assessment of Joints Score) and histological level. Results: There was no significant difference of the Implant Gross Assessment score between the SCF and SCS groups. All implants showed excellent capsular ingrowth at the periphery. Dislocation, extrusion and tears occurred in part of the specimen due to biomechanical problems caused by soft tissue quality. The mean Gross Assessment of Joint Changes Score of the groups SCF and SCS was not statistically different. Cartilage damage was significantly more severe in joints with implants than in non-operated joints and sham controls, but less pronounced than in menisectomy controls. Histological evaluation showed residual scaffold with an associated foreign body response in all implants. Fibrous tissue was present in all implants, in contrast small foci of cartilaginous differentiation were more common in the cell-seeded constructs. Discussion: At 4 months regenerative meniscal tissue was present but immature. The present study showed that strong biomechanical scaffold properties are a required to allow guided tissue regeneration and maturation under loading conditions. Cell seeding of the scaffold encourages cartilaginous differentiation. Modification of the scaffold and the cell-seeding technique will be investigated in further studies.