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Purpose: To compare the safety and efficacy of two different approaches of platelet-rich plasma (PRP) production methods as intra-articular injection treatment for knee cartilage degenerative lesions and osteoarthritis (OA)., Methods: The study involved 144 symptomatic patients affected by cartilage degenerative lesions and OA. Seventy-two patients were treated with 3 injections of platelet concentrate prepared with a single-spinning procedure (PRGF), the other 72 with 3 injections of PRP obtained with a double-spinning approach. The patients were evaluated prospectively at the enrollment and at 2, 6, and 12 months' follow-up with IKDC, EQ-VAS and Tegner scores; adverse events and patient satisfaction were also recorded., Results: Both treatment groups presented a statistically significant improvement in all the scores evaluated at all the follow-up times. Better results were achieved in both groups in younger patients with a lower degree of cartilage degeneration. The comparative analysis showed similar improvements with the two procedures: in particular, IKDC subjective evaluation increased from 45.0 ± 10.1 to 59.0 ± 16.2, 61.3 ± 16.3, and 61.6 ± 16.2 at 2, 6, and 12 months in the PRGF group, and from 42.1 ± 13.5 to 60.8 ± 16.6, 62.5 ± 19.9, and 59.9 ± 20.0 at 2, 6, and 12 months in the PRP group, respectively. Concerning adverse events, more swelling (P = 0.03) and pain reaction (P = 0.0005), were found after PRP injections., Conclusions: Although PRP injections produced more pain and swelling reaction with respect to that produced by PRGF, similar results were found at the follow-up times, with a significant clinical improvement with respect to the basal level. Better results were achieved in younger patients with a low degree of cartilage degeneration., Level of Evidence: II.