INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) maintains end-organ perfusion in critically ill patients with cardiac or respiratory failure; however, ECMO cannulation in the extremities has been associated with significant limb ischemia and risk of compartment syndrome. Current literature on ECMO and fasciotomies is limited to small single-center retrospective studies. This study aimed to (1) compare the incidence of postoperative outcomes and mortality in patients undergoing fasciotomy while on ECMO to those of non-fasciotomy ECMO patients, and (2) assess the difference in adjusted mortality risk between the two groups. HYPOTHESIS: We hypothesized that patients undergoing fasciotomy while on ECMO would have significantly higher odds of in-hospital mortality than non-fasciotomy ECMO patients after adjustment for perioperative variables. METHODS: We conducted a retrospective review of NIS from January 1st, 2012-September 30, 2015 for all hospitalizations involving ECMO and stratified them into two cohorts based on whether they underwent fasciotomy after ECMO. Patient baseline characteristics, in-hospital procedures, and postoperative outcomes were compared between the two cohorts. Logistic regression was used to assess in-hospital mortality risk between the two cohorts adjusting for age, sex, Elixhauser score, and perioperative procedures and non-fasciotomy perioperative morbidity. RESULTS: There were 7,085 estimated eligible discharges between 2012 and 2015 identified, 149 (2.1%) of which underwent fasciotomy following ECMO. One hundred and thirteen of the 149 hospitalizations (77%) in the fasciotomy cohort resulted in in-hospital mortality, compared to 3,805 of the 6,936 (55%) in the non-fasciotomy cohort. There were no differences in rates of transfusion (p=0.290), length of stay (p=0.282), or discharge disposition (p=0.126) between the two cohorts. In the logistic regression model, the fasciotomy cohort had a higher odds of in-hospital mortality than non-fasciotomy cohort (OR, 2.5; 95% CI, 1.1-5.6). DISCUSSION: Operative treatment of acute compartment syndrome for patients on ECMO therapy is associated with significantly increased mortality and morbidity. Whether fasciotomy is a marker of sickness or represents a cause-and-effect relationship is unknown and future should investigate the role of non-operative treatment of compartment syndrome on mortality in this population. LEVEL OF EVIDENCE: III; Prognostic.