Background: Hemolysis is a frequent complication in patients with sepsis, ARDS, or extracorporeal membrane oxygenation (ECMO). Haptoglobin (Hp) can scavenge released cell-free hemoglobin (CFH). Hemolysis and low plasma concentrations of Hp may be independently associated with mortality in critically ill patients. Methods: This study used a retrospective analysis of 435 patients with ARDS and veno-venous ECMO therapy, admitted to a tertiary ARDS referral center (01/2007-12/2018). Hp depletion was defined as decrease in plasma Hp concentration <0.39 g/L within the first week after ECMO initiation. Patients with Hp depletion were compared to patients without Hp depletion. The primary endpoint was 28-day mortality. Secondary endpoints included organ dysfunction-free, renal replacement therapy-free, vasopressor-free, and ECMO-free composites. Results: Patients with Hp depletion (n = 269) had a significantly higher mortality 28 days after ECMO initiation compared to patients without Hp depletion (43.5% [95% CI 37.52-49.66] vs. 25.3% [19.03-32.74], P < 0.001). Furthermore, patients with Hp depletion had fewer organ dysfunction-free days (subdistribution hazard ratio [SHR] 0.35 [95% CI 0.25-0.50], P < 0.001), lower chances for successful weaning from renal replacement therapy (SHR 0.50 [0.32-0.79], P < 0.001), vasopressor therapy (SHR 0.39 [0.28-0.54], P < 0.001), and ECMO therapy (SHR 0.41 [0.30-0.57], P < 0.001) within 28 days after ECMO initiation. Patients with initial Hp <0.66 g/L had higher risks for Hp depletion than patients with initial Hp ≥0.66 g/L. Conclusion: Patients with Hp depletion within the first week of ECMO therapy might benefit from close monitoring of hemolysis with early detection and elimination of the underlying cause. They might be potential candidates for future Hp supplementation therapy to prevent overload of the CFH-scavenger system.