Extracorporeal membrane oxygenation (ECMO) protocols generally require systemic anticoagulation with heparin to prevent circuit thrombosis. The prevalence, risk factors, and outcomes of heparin resistance in this setting are ill-defined. To better understand the prevalence and clinical consequences of heparin resistance in this population, we conducted a retrospective analysis of all patients treated with ECMO at a single academic medical center between 2016 and 2019. Univariate and multivariate analyses were used to evaluate predictors and outcomes of heparin resistance. Of 67 patients in our study, 50.7% met the threshold for heparin resistance for at least 1 day, which was managed in all cases with increases in heparin dose. Patients with heparin resistance were more likely to be male (82.4% vs. 48.5%, p = 0.005) and to have a higher mean platelet count (132 vs. 104 × 103/mL, p = 0.027) compared with those without heparin resistance. Multivariate logistic regression found no significant association between the development of heparin resistance and rates of thrombosis, hemorrhage, or overall survival. Additional prospective studies are required to clarify the clinical implications of heparin resistance in this population.