One hundred and twenty patients with massive subchondral knee defects were randomized to the intervention group undergoing arthroscopic subchondral drilling followed by peripheral blood stem cell and hyaluronic acid injections (n=60) or a control group receiving hyaluronic acid injections and physiotherapy (n=60). The coprimary endpoints were the subjective International Knee Documentation Committee (IKDC) and Knee Injury and Osteoarthritis Outcome Score (KOOS) pain subdomain measured at 24 months follow-up. At 24 months the mean IKDC scores and change in IKDC scores were significantly improved in the intervention group compared to the control group. The KOOS pain subscore also significantly improved in the intervention group compared to the control group. The study was stopped early due to the significant difference in outcomes and absence of adverse events in the treatment arm.