376 patients diagnosed with chronic primary knee osteoarthritis were randomized to receive autologous conditioned serum, hyaluronan, or saline injections. The purpose of this study was to compare the clinical efficacy and safety of autologous conditioned serum to the other treatments. Significantly greater improvements were displayed by the autologous conditioned serum group in terms of WOMAC, VAS pain, and SF-8 HRQL scores at weeks 7, 13, and 26 and in global patient assessment of treatment efficacy at 13 and 26 weeks, compared to the other two groups. Overall adverse events were significantly lower in the autologous conditioned serum and saline groups and the additional 2-year follow-up was consistent with the previous quality of life and clinical outcome results.