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Background: We evaluated critically ill patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) due to cardiac arrest (CA) with respect to baseline characteristics and laboratory assessments, including lactate and lactate clearance for prognostic relevance. Methods: The primary endpoint was 30-day mortality. The impact on 30-day mortality was assessed by uni- and multivariable Cox regression analyses. Neurological outcome assessed by Glasgow Outcome Scale (GOS) was pooled into two groups: scores of 1–3 (bad GOS score) and scores of 4–5 (good GOS score). Results: A total of 93 patients were included in the study. Serum lactate concentration (hazard ratio (HR) 1.09; 95% confidence interval (CI) 1.04–1.13; p < 0.001), hemoglobin, (Hb; HR 0.87; 95% CI 0.79–0.96; p = 0.004), and catecholamine use were associated with 30-day-mortality. In a multivariable model, only lactate clearance (after 6 h; OR 0.97; 95% CI 0.94–0.997; p = 0.03) was associated with a good GOS score. The optimal cut-off of lactate clearance at 6 h for the prediction of a bad GOS score was at ≤13%. Patients with a lactate clearance at 6 h ≤13% evidenced higher rates of bad GOS scores (97% vs. 73%; p = 0.01). Conclusions: Whereas lactate clearance does not predict mortality, it was the sole predictor of good neurological outcomes and might therefore guide clinicians when to stop ECPR. [ABSTRACT FROM AUTHOR]