Chronic steroid and immunosuppressant use have been shown to increase the risk for postoperative complications in orthopaedic surgery. Further understanding of the risks of immunosuppression is necessary to aid in risk stratification and patient counseling. However, these risks have not yet been explored in ankle fracture patients. Thus, the purpose of this study is to determine whether patients taking immunosuppressives are at an increased risk for morbidity and mortality following open reduction and internal fixation (ORIF) of ankle fractures. Patients undergoing operative treatment for ankle fractures from 2006 to 2018 were identified in the National Surgical Quality Improvement Program (NSQIP) database. Patients were categorized based on their use of immunosuppressive medications. Postoperative outcomes assessed included superficial surgical site infections, deep surgical site infections, organ space infections, wound dehiscence, pneumonia, unplanned intubation, pulmonary embolism, urinary tract infection, renal failure, blood transfusion requirement, deep vein thrombosis, sepsis, cardiac arrest, extended length of hospital stay, readmission, reoperation, and mortality. Univariate and multivariate analyses were performed. In total, 10,331 patients underwent operative treatment for ankle fracture. 10,153 patients (98.3%) were not taking immunosuppressants and 178 (1.7%) were taking these medications. In multivariate analysis, patients taking immunosuppressants were at increased risk of pulmonary embolism (OR 4.382; p=0.041) and hospital readmission (OR 2.131; p=0.021). Use of immunosuppressive medications is an independent risk factor for pulmonary embolism and readmission following ORIF for ankle fractures. Notably, no association with wound complications, infections, or sepsis was identified.Copyright © 2023. Published by Elsevier Inc.