Background <p>The relationship between lactate-to-albumin ratio (LAR) and mortality in patients with cardiogenic etiology undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) remains unclear. Against this backdrop, the present study is designed to explore the correlation between LAR and 28-day mortality among patients supported by VA-ECMO.</p> Methods <p>This study was a multicenter retrospective study that included patients undergone VA-ECMO from Medical Information Mart for Intensive Care-IV (MIMIC-IV) database and the First People’s Hospital of Kunshan in China. The primary outcome was 28-day in-hospital mortality. Kaplan-Meier survival analysis, multivariable Cox regression, and restricted cubic splines (RCS) were used to assess the association between LAR and mortality. Model performance was assessed using receiver operating characteristic (ROC) curve analysis. Subgroup analyses were used to test interactions. </p> Results <p>In total, 154 patients (78 patients in Chinese database and 76 patients in MIMIC database) participated in this study. LAR were associated with 28-days mortality significantly as a continuous variable (HR: 1.16, 95% CI: 1.05 ~ 1.28, P &lt; 0.01) or categorical variable (HR 5.67, 95% CI: 1.58 ~ 17.23, P &lt; 0.01) in Chinese database. The same result was also observed in the MIMIC group. RCS analysis model illustrated the linear relationship between higher LAR and 28-day mortality in patients with VA-ECMO. ROC analysis suggest that LAR holds less predictive value, when combined with APACHII or APSIII scores the improvement is also small.</p> Conclusions <p>LAR is associated with 28-day mortality in patients with cardiogenic etiology undergone VA-ECMO which offers valuable prognostic marker.</p>