Background <p>The ratio of pulse-oximetric peripheral oxygen saturation to fraction of inspired oxygen (SpO₂/FiO₂) has been proposed as additional hypoxemia criterion in a new global definition of acute respiratory distress syndrome (ARDS). This study aims to evaluate the clinical and theoretical limitations of the SpO₂/FiO₂-ratio when using it to classify patients with ARDS and to follow disease progression.</p> Methods <p>Observational cohort study of ARDS patients from three high-resolution Intensive Care Unit databases, including our own database ICU Cockpit, MIMIC-IV (Version 3.0) and SICdb (Version 1.0.6). Patients with ARDS were identified based on the Berlin criteria or ICD 9/10-codes. Time-matched datapoints of SpO₂, FiO₂ and partial pressure of oxygen in arterial blood (PaO₂) were created. Severity classification followed the thresholds for SpO₂/FiO₂ and PaO₂/FiO₂ of the newly proposed global definition.</p> Results <p>Overall, 708 ARDS patients were included in the analysis. ARDS severity was misclassified by SpO₂/FiO₂ in 33% of datapoints, out of which 84% were classified as more severe. This can be partially explained by imprecision of SpO₂ measurement and equation used to transform SpO₂/FiO₂ to PaO₂/FiO_2. A high dependence of SpO₂/FiO₂-ratio on FiO₂ settings was found, leading to major treatment effect and limited capability for tracking change in ARDS severity, which was achieved in less than 20% of events.</p> Conclusions <p>The use of SpO₂/FiO₂ interchangeably with PaO₂/FiO₂ for severity classification and monitoring of ARDS is limited by its inadequate trending ability and high dependence on FiO₂ settings, which may influence treatment decisions and patient selection in clinical trials.</p>