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RATIONALE Supplemental oxygen is among the most commonly administered therapies in intensive care units. High supplemental oxygen exposure has been associated with harm in observational human studies and animal models. Yet no consensus exists regarding which dose and duration of high oxygen constitutes harmful hyperoxemia, and little is known regarding the clinical factors that predict potentially injurious exposure. OBJECTIVES To determine the level and duration of arterial oxygen (PaO2) associated with mortality among mechanically ventilated patients, and to identify the clinical factors that predict this exposure. METHODS We performed a retrospective cohort study of patients who received invasive mechanical ventilation at a single academic institution in 2017 and 2018. We used a generalized additive model to visualize the relationship between the measured PaO2 via arterial blood gases (ABGs) and 30-day mortality. We used multivariable logistic regression to identify patient- and hospital-level factors that predict exposure to harmful hyperoxemia. RESULTS We analyzed 2,133 patients with 33,310 ABGs obtained during mechanical ventilation. We identified a U-shaped relationship between PaO2 and mortality, where PaO2 was positively correlated with mortality above a threshold of 200 mmHg. 1,184 patients (55.5%) had at least one PaO2 level above this threshold. If patients spent an entire day exposed to PaO2 > 200 mmHg, they had 2.19 (95% CI 1.33 - 3.60, p = 0.002) greater odds of 30-day mortality in an adjusted analysis. Any exposure to severe hyperoxemia (PaO2 > 200 mmHg), was associated with mortality (OR 1.29, 95% CI 1.04 - 1.59, p = 0.021). The strongest clinical predictor of severe hyperoxemia exposure was the identity of the ICU in which mechanical ventilation was delivered. CONCLUSIONS Exposure to high arterial oxygen concentrations is common among mechanically ventilated patients, and the dose and duration of PaO2 ≥ 200 mmHg is associated with mortality. Severe hyperoxemia is highly variable across ICUs, and is far more common in clinical practice than in recent randomized trials of oxygen targeting strategies. Efforts to minimize this common and injurious exposure level are needed.