Background: Osteochondral lesions of the talus (OLT) treatment is widely debated when the lesion size exceeds 150 mm2. The aim of this study was to assess functional outcome and satisfaction rates of the autologous matrix-related chondrogenesis (AMIC) technique and compare the outcomes for OLTs larger than 150 mm2 that were classified as primary, primary with local tumor-related OLT, or revision cases. Methods: A total of 77 patients who were operated by AMIC were included. The average age of the population was 39.6 years. The mean body mass index (BMI) was 27.2. Smoker rate was 28.5% of the population. Forty-two patients were primary cases, 14 patients had primary with local tumor-related OLT, and 18 patients were revision cases. Overall and subgroup functional outcomes were evaluated by visual analog scale (VAS) and Foot and Ankle Disability Index (FADI) scores. Satisfaction rates were queried, and failures were recorded. Results: After a median follow-up of 32 months, the score improvement for primary, primary with local tumor-related, and revision group were for VAS, 5.4 ± 0.4, 5.6 ± 0.7, and 3.6 ± 0.8, and for FADI, 46.5 ± 3.8, 45.3 ±6.5, and 26.6 ± 6.7, respectively ( P < .001). Intergroup comparison showed greater improvement for the primary OLT group when compared to the revision group ( P < .001). The failure rates for the primary, primary with local tumor-related, and revision group were 4.8%, 11.8%, and 38.9%, respectively. Conclusion: AMIC procedure provides good functional outcome and satisfactory rates in patients with primary and primary with local tumor-related OLT larger than 150 mm2, but in revision cases, the AMIC success rate was not encouraging as all had advanced OLT operative interventions. Level of Evidence: Level III, therapeutic retrospective study.