In this study, we investigated the efficacy of the transplantation of autologous articular chondrocytes seeded onto a hyaluronan-based scaffold, known as Hyaff(®)-11, on the treatment of early cartilage lesions in a rabbit osteoarthritis (OA) model. The hypothesis of the study was that this treatment could enhance cartilage repair after OA induction. OA was surgically induced by Anterior Cruciate Ligament Transection (ACLT) in thirty rabbits. Animals were divided into three groups, according to treatment: group 1: ACLT; group 2: Chondrocytes+Hyaff-11; and group 3: Hyaff-11 alone. The animals were euthanized, respectively, at 3 and 6 months after the treatment. Histomorphometrical analyses were performed by means of fibrillation index, cartilage thickness, and subchondral bone thickness evaluations. Histological appearance was scored according to Modified Kraus' Mankin and Osteoarthritis Research Society International (OARSI) scores. Immunohistochemical analyses were carried out for type I and II collagens, MMP-1, and MMP-3. A comparison between groups and follow-up for each outcome was performed with the general linear model with Sidak correction. Histomorphometrical evaluations at 3 and 6 months demonstrated that OA lesions became significantly worse followed by Hyaff-11 treatment, whereas Chondrocytes+Hyaff-11 treatment had the best overall subjective grade. Overall raw histological scores demonstrated a significant improvement with chondro-hyaluronic acid (HA) treatment at 3 months compared with HA in cartilage repair processes. Immunohistochemical analyses displayed a strong positivity for type II collagen in the Chondrocytes+Hyaff-11group at 3 months compared with the HA group. No staining was observed in MMP-3 expression in this group at any experimental point. The use of Chondrocytes+Hyaff-11 for the treatment of early OA lesions produced, already at 3 months, a repair tissue showing better macroscopic, histological, and immunohistochemical results than those observed after Hyaff-11 treatment. Thus, the transplantation of Chondrocytes+Hyaff-11 would seem to be advocated in the very early stage of the OA disease when a precocious action is mandatory.