Rationale: There is conflicting evidence on harm related to exposure to supra-physiologic arterial oxygen tensions (hyperoxemia) in critically ill patients. Objectives: To examine the association between longitudinal exposure to hyperoxemia and mortality in patients admitted to intensive care units (ICUs) in 5 UK University Hospitals. Methods: Retrospective cohort of ICU admissions between 31st January 2014 - 31st December 2018, from the National Institute of Health Research Critical Care Health Informatics Collaborative (CC-HIC). Multivariable logistic regression modelled death in ICU by exposure to hyperoxemia. Measurements: Subsets with oxygen exposure windows of 0-1, 0-3, 0-5 and 0-7 days were evaluated, capturing 19,515, 10,525, 6,360 and 4,296 patients, respectively. Hyperoxemia dose was defined as the area between the PaO2 time curve and a boundary of 13.3 kPa (100 mmHg) divided by the hours of potential exposure (24, 72, 120, or 168 hours). Main Results: An association was found between exposure to hyperoxemia and ICU mortality [odds ratios (95% compatibility intervals); 1.15 (0.95-1.38), p = 0.15; 1.35 (1.04-1.74), p = 0.02; 1.5 (1.07-2.13), p = 0.02; and 1.74 (1.11-2.72), p = 0.02 for exposure windows of 0-1, 0-3, 0-5 and 0-7 days’ duration, respectively. However, a dose-response relationship was not observed. There was no evidence to support a differential effect between hyperoxemia and either a respiratory diagnosis or mechanical ventilation. Conclusions: An association between hyperoxemia and mortality was observed in our large, unselected multicenter cohort. The absence of a dose-response relationship weakens causal interpretation. Further experimental research is warranted to elucidate this important question.