Osteoarthritis represents an important social economic burden with a high incidence worldwide. Conservative management of knee OA consists in several therapeutic options: pharmacologic therapy such as analgesics, non-steroid and steroid anti-inflammatory drugs, physical therapy, and injective therapy with hyaluronic acid (HA) and platelet-rich plasma injections (PRP). The aim of our study is to evaluate the effect of combined autologous PRP and HHA (Hybrid Hyaluronic Acid) viscosupplementation on clinical outcomes of patients with knee OA, by assessing the subjects before and after injective treatment. The study was conducted on 60 patients with an age between 40 and 70 years old affected by unilateral symptomatic knee osteoarthritis (stage II and III of Kellgren-Lawrence scale) nonresponsive to pharmacologic and rehab treatment. We divided the patients in two groups, and we treated the group A with injection of HHA and group B with HHA+PRP. Each patient received 3 injections at an interval of 1 week for 3 consecutive weeks. The patients were evaluated by the Knee Injury and Osteroartrhitis Outcome Score (KOOS) and Visual Analog Scale (VAS) at 3, 6 and 12 months after treatment. Statistical comparison between groups showed a significantly better result for the group B concerning the KOOS value, at 3 months and at 6 months. This difference, although clinically relevant, lost the statistical significance at 12 months. The VAS trend differently showed a significant difference at 3 and 12 months, while at 6 months the superiority of group B did not achieve statistical significance. Few studies investigated the effects of HA+PRP combined treatment for knee OA. Numerous studies demonstrated the efficacy of HA injection therapy in knee OA for a clinical point of view, reducing the pain and improving the quality of life. PRP preparations also improved functional outcome scores compared to hyaluronic acid and placebo in patients affected by knee OA. Based on our results we can conclude that the combined PRP and HHA treatment is not only a safe and efficacious procedure which can provide functional benefit but is also significantly better than HHA injective therapy alone, as demonstrated by the comparison within our cohort.