OBJECTIVES: Autologous peripheral blood-derived orthobiologics like platelet-rich plasma (PRP) have been gaining in popularity in symptomatic relief of knee osteoarthritis (OA). Autologous protein solution (APS) that is derived from PRP offers higher levels of growth factors and anti-inflammatory cytokines, reducing inflammation and improve cartilage quality. Additionally, hyaluronic acid (HA) has shown efficacy in relieving OA symptoms. This study aims to assess the clinical outcomes of combined APS and HA therapy, particularly a presence of pathological site pain (PSP) during injection as a predictive sign for clinical response. METHODS: Patients with early-stage OA received APS and HA injections. Patients were evaluated pre-injection and at 1-year follow-up. Patient-reported outcomes were assessed with WOMAC, KOOS, VAS pain score, and SF-36 survey. The OMERACT-OARSI criteria determined treatment effects. Satisfaction and expectation fulfillment were also recorded. RESULTS: 32 patients were included in the final analysis. Statistically significant improvements were observed in all outcome scores at 1 year. The responder rate per OMERACT-OARSI criteria was 65.6 %, with 96.9 % of patients reporting satisfaction and expectation fulfillment. When comparing responder-rates and improvement in patient-reported outcome measures with other studies, combined therapy does not appear to confer additional therapeutic benefit over APS monotherapy at the 1-year mark. No severe adverse events related to the injections were reported. Patients with PSP had significantly better outcomes in terms of pain, stiffness, symptoms, activities of daily living, quality of life, as well as statistically significantly higher satisfaction rates of expectation fulfilment. CONCLUSIONS: At 1-year post-injection, the APS and HA combination significantly improved WOMAC, KOOS, SF-36 PCS, and VAS scores, with a high rate of patient satisfaction. PSP during injection could possibly be predictive of better outcomes and expectation fulfilment. LEVEL OF EVIDENCE: Level III.