Background: Autologous osteoperiosteal transplantation (AOPT) using graft harvested from the iliac crest is used to treat large cystic osteochondral lesions of the talus (OLTs). However, no studies have compared clinical and radiologic outcomes between AOPT and autologous osteochondral transplantation (AOCT) using graft harvested from the nonweightbearing zone of the femoral condyle of the ipsilateral knee in patients with large cystic OLTs. Purpose: To compare clinical and radiologic outcomes between patients undergoing AOPT and those undergoing AOCT for large cystic OLTs. Study Design: Cohort study; Level of evidence, 3. Methods: Between March 2015 and March 2018, patients who underwent AOCT and AOPT to treat medial large cystic OLTs (>10 mm) were retrospectively evaluated. For comparability, the 2 groups were matched 1:1 based on their characteristics, including sex, age, body mass index, side of injury, follow-up period, and the preoperative cyst volume. After propensity score matching, 23 patients were enrolled in each group for the analysis. Clinical outcomes were assessed using the visual analog scale (VAS), the American Orthopaedic Foot & Ankle Society (AOFAS) score, and the Tegner score. Donor-site morbidity was recorded according to the symptoms, including pain, stiffness, swelling, and discomfort. In addition, the Lysholm score was used to assess the most common knee donor-site morbidity. Radiologic outcomes were evaluated using the magnetic resonance observation of cartilage repair tissue (MOCART) score, and the International Cartilage Regeneration & Joint Preservation Society (ICRS) score was obtained during second-look surgery. Results: The mean follow-up period was about 48 months. There were no significant differences in patient characteristics and lesion volumes between groups. Postoperative ankle pain VAS score, AOFAS score, and Tegner score were not significantly different between groups at final follow-up. Total donor-site morbidity (P = .004) and discomfort morbidity (P = .009) were significantly lower in the AOPT group than in the AOCT group. However, the Lysholm score showed no significant difference between the donor knee and the opposite knee (P = .503) in the AOCT group. The MOCART and ICRS scores were not significantly different between groups. Conclusion: Clinical and radiologic outcomes of patients who underwent AOPT from the iliac crest were found to be comparable with those of patients who underwent AOCT from the ipsilateral knee for the treatment of medial large cystic OLTs. These results may be helpful for orthopaedic surgeons to decide appropriate treatments for patients with large cystic OLTs.