The aim of this prospective observational study was to assess the 3-year clinical outcome of distal realignment and membrane-seeded autologous chondrocyte implantation (MACI) in selected patients with patellofemoral malalignment and large, isolated, patellar cartilage lesions. Twelve patients (14 knees; 6 females, 6 males; mean age 31 years) with Fulkerson type II patellofemoral malalignment (lateralized and tilted patella) and Outerbridge grade III-IV isolated patellar cartilage lesions were treated. All had tibial tuberosity and trochlear sulcus >20 mm on a preoperative CT scan and a cartilage defect >3 cm2. Patients with Outerbridge grade III-IV trochlear cartilage lesions, those with rheumatic, infective or neoplastic conditions, or ligament instability, diabetes or obesity and those aged >40 years were excluded. Follow-up was at 36 months. Patients were enrolled after diagnostic arthroscopy. Cartilage was harvested and sent for culture. After a mean period of 30 days (range 25-40) patients underwent transfer of the tibial tuberosity according to Fulkerson associated with a MACI procedure. Clinical assessment was performed with the Kujala, Lysholm, Tegner and Modified Cincinnati scores. The Patient Satisfaction Survey was administered at 36 months. Consistently improved knee function and activity levels were reflected by significantly increased Kujala, Lysholm, Tegner and Modified Cincinnati scores at 36 months. The significant clinical improvement support the value of associating distal realignment and autologous chondrocyte implantation in treating large, isolated, patellar cartilage lesions associated with patellofemoral malalignment.