BACKGROUND Osteochondral lesions of talus (OLT) are among the most common ankle problems. Platelet-rich plasma (PRP) and prolotherapy (PrT) are 2 successful injection-based techniques for treatment of chronic musculoskeletal problems. The aim of the present study was to compare PRP and PrT injections for the management of OLT. MATERIAL AND METHODS This was a retrospective cohort study of 49 patients with OLT symptoms of more than 6 months who had been refractory to 3 months of treatment using conservative methods. The patients were divided into 2 groups: PrT injections (PrT group, n=27) or PRP injections (PRP group, n=22). The patients were given 3 injections of 4 mL solution into periarticular and intra-articular ankle joint spaces. After treatment, patients were evaluated via Visual Analogue Scale (VAS), American Orthopedic Foot and Ankle Society Score (AOFAS), and Ankle Osteoarthritis Scale (AOS) at baseline and 21-, 90-, 180-, and 360-day follow-up periods. RESULTS Both PRP and PrT treatments resulted in greater improvement in pain and ankle functions at follow-up periods extending to 1 year (P<0.001) and there was no difference between the groups for the outcomes at follow-up periods (P>0.05). Excellent or good outcomes were reported by 88.8% of the patients in PrT group and 90.9% of the patients in PRP group. CONCLUSIONS Both PRP and PrT are efficient and safe methods in treatment of OLT. PrT offers advantages of less cost and minimal invasiveness.