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Both patient characteristics and intraoperative factors have been associated with a higher risk of stroke after cardiac surgery. We hypothesized that poor systemic oxygenation in the perioperative period is associated with increased risk of stroke following cardiopulmonary bypass.In this study of 251 adult patients who underwent cardiopulmonary bypass procedures at a single center from 2003 to 2006, cases (patients with a postoperative stroke at least 24 hours after surgery) were matched 1:2 to controls without stroke. Minimum and average partial pressure of oxygen in arterial blood (PaO2) values, from arterial blood gas values during and up to 24 hours after surgery, were evaluated as continuous and categorical predictors. Conditional logistic regression models adjusted for potential confounders (demographics, comorbidities, and intraoperative variables) were used to evaluate associations between PaO2 variables and stroke status.Lower nadir PaO2 values were associated with postoperative stroke, with estimated odds of stroke increasing over 20% (adjusted odds ratio [OR], 1.23; 95% confidence interval [CI], 1.07–1.41) per 10 mm Hg lower nadir PaO2, and similarly increased odds of stroke per lower quartile of nadir PaO2 (OR, 1.60; 95% CI, 1.19–2.16). When average PaO2 was considered, odds of stroke was also increased (adjusted OR, 1.39 per lower quartile of mean PaO2; 95% CI, 1.05–1.83). Having a nadir PaO2 value in the lowest versus any other quartile was associated with an estimated 2.41-fold increased odds of stroke (95% CI, 1.22–4.78). Quartile of nadir but not average PaO2 results remained significant after adjustment for multiple comparisons.Odds of stroke after cardiac surgery are increased in patients with a low minimum PaO2 within 24 hours of surgery. Results should be validated in an independent cohort. Further characterizing the underlying etiology of hypoxic episodes will be important to improve patient outcomes.