Two-hundred patients with moderate, symptomatic knee osteoarthritis were randomized to receive an intra-articular injection of amniotic suspension allograft (ASA; n=68), hyaluronic acid (HA; n=64) or normal saline (n=68). Outcomes of interest included the change from baseline at 12 months in the Knee Injury and Osteoarthritis Outcome Score (KOOS) subsets (pain; symptoms; activities of daily living; sports and recreation; quality of life), as well as Visual Analog Scale (VAS) pain scores overall, during strenuous work, during sedentary work, and during normal daily living. Immunoglobulin levels and C-reactive protein (CRP) levels, as well as the presence of serum anti human leukocyte antigen (HLA) levels, were recorded up to 6 months post-injection. Results revealed significantly greater improvement in all KOOS subsets and VAS pain scores from baseline at 12 months in the ASA group compared to the HA and saline groups. However, severe patient drop-out after 3 months in the HA and saline groups was observed, and a last observation carried forward method was used for analysis. No significant differences between the ASA group and the HA and saline groups were observed in all immunoglobulin levels, with the exception of IgE at 6 months which was significantly higher in the saline group vs ASA. The rate of treatment-emergent adverse event cases was similar between the ASA (2.9%) and HA (3.1%) groups, with none observed in the saline group.