Background: Osteoarthritis is the most prevalent type of arthritis, which significantly impacts the patient's mobility and quality of life. Pharmacological treatments for osteoarthritis, such as corticosteroids, produce an immediate reduction of the patient's pain as well as an improvement in the patient's mobility and quality of life, but with a limited long-term efficacy. In this context, platelet-rich plasma (PRP) infiltrations represent a therapeutic tool due to its trophic properties and its ability to control inflammatory processes, especially in musculoskeletal applications. The aim of this study is to evaluate and compare the clinical benefits of PRP when injected intra-articularly vs a commonly used corticosteroid (CS, triamcinolone acetonide, Kenalog®) in patients affected by mild to moderate symptomatic knee osteoarthritis. Methods: Forty patients affected by symptomatic radiologically confirmed knee osteoarthritis (Kellgren-Lawrence grades II-III) were enrolled in this randomized study. Patients randomized in the PRP group (n = 20) received an intra-articular injection of PRP (8 mL) while patients randomized in the CS group (n = 20) received an intra-articular injection of triamcinolone acetonide (1 mL of 40 mg/mL) plus lidocaine (5 mL of 2%). The pain and function of the target knee were evaluated by the VAS, IKDC, and KSS scales at the baseline (V1), 1 week (V2), 5 weeks (V3), 15 weeks (V4), 30 weeks (V5), and 1 year (V6) after treatment.