Orthobiologics are biologically-derived materials intended to promote bone formation and union. We review evi-dence on effectiveness and harms of orthobiologics compared to no orthobiologics for foot and ankle arthrodesis. We searched multiple databases (1995-2019) and included clinical trials and other studies with concurrent con-trols, English language, and reporting patient-centered outcomes, union/time to union, costs/resource utilization, or harms. Studies were organized by orthobiologic used. We describe quality and limitations of available evidence but did not formally rate risk of bias or certainty of evidence. Most of the 21 studies included were retrospective chart reviews with orthobiologics used at surgeon's discretion for patients considered at higher risk for nonunion. Ten studies compared autologous bone graft versus no graft and 2 compared remote versus local graft with few studies of other orthobiologics. All studies reported a measure of fusion and about half reported on function/qual-ity of life. Few studies reported harms. Due to limited reporting, we were unable to assess whether effectiveness varies by risk factors for nonunion (eg, age, gender, smoking status, obesity, diabetes) or whether orthobiologics were cost-effective. Available evidence is of poor quality with small sample sizes, inadequate reporting of risk fac-tors for nonunion, variations in orthobiologics, surgical techniques used, and outcome assessment, and potential selection bias. Research is needed to adequately inform surgeons about benefits and harms and guide patient selection for use, or type, of orthobiologics. Careful assessment of individual patient risk for nonunion is critical prior to orthobiologic use. Published by Elsevier Inc. on behalf of the American College of Foot and Ankle Surgeons.