There is conflicting evidence on harm related to exposure to supraphysiologic Pa (hyperoxemia) in critically ill patients. To examine the association between longitudinal exposure to hyperoxemia and mortality in patients admitted to ICUs in five United Kingdom university hospitals. A retrospective cohort of ICU admissions between January 31, 2014, and December 31, 2018, from the National Institute of Health Research Critical Care Health Informatics Collaborative was studied. Multivariable logistic regression modeled death in ICU by exposure to hyperoxemia. Subsets with oxygen exposure windows of 0 to 1, 0 to 3, 0 to 5, and 0 to 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 Pa time curve and a boundary of 13.3 kPa (100 mm Hg) divided by the hours of potential exposure (24, 72, 120, or 168 h). An association was found between exposure to hyperoxemia and ICU mortality for exposure windows of 0 to 1 days (odds ratio OR, 1.15; 95% compatibility interval CI, 0.95-1.38;  = 0.15), 0 to 3 days (OR 1.35; 95% CI, 1.04-1.74;  = 0.02), 0 to 5 days (OR, 1.5; 95% CI, 1.07-2.13;  = 0.02), and 0 to 7 days (OR, 1.74; 95% CI, 1.11-2.72;  = 0.02). 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. 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.