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<b>Background/Objectives:</b> Extracorporeal membrane oxygenation (ECMO) use has increased worldwide, yet in-hospital mortality among adult recipients remains substantial. Large-scale evidence examining patient- and treatment-related factors associated with mortality in real-world settings is still limited. This study aimed to quantify in-hospital mortality and identify factors associated with mortality among adults receiving ECMO using a nationwide cohort in Taiwan. <b>Methods:</b> We conducted a retrospective nationwide cohort study using Taiwan's National Health Insurance Research Database, including adults (≥18 years) who received ECMO during hospitalization between 2011 and 2020. ECMO indication groups were defined using ICD-9-CM (before 2016) and ICD-10-CM (2016 onward) codes and further classified into four mutually exclusive categories. Multivariable logistic regression was used to examine factors associated with in-hospital mortality. <b>Results:</b> Among 15,151 adults treated with ECMO, 9657 (63.7%) died during hospitalization. In multivariable analyses, higher odds of in-hospital mortality were associated with older age, higher comorbidity burden (Charlson Comorbidity Index ≥3), and use of multiple ECMO machines (≥2). Compared with patients without cardiopulmonary indications, those classified as cardiogenic shock alone or combined respiratory failure and cardiogenic shock had lower adjusted odds of in-hospital mortality. Longer hospital length of stay was inversely associated with in-hospital mortality, reflecting differing care trajectories among ECMO recipients. <b>Conclusions:</b> In this nationwide real-world cohort of adult ECMO recipients, in-hospital mortality was high, and mortality risk was associated with patient age, comorbidity burden, ECMO treatment complexity, and diagnosis-based indication classification. These findings provide population-level insight into mortality patterns and may inform risk communication and system-level planning for ECMO care.