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The current study was designed to determine the relation between preoperative cerebral oxygen saturation (Sco2), variables of cardiopulmonary function, mortality, and morbidity in a heterogeneous cohort of cardiac surgery patients.In this study, 1,178 consecutive patients scheduled for on-pump surgery were prospectively studied. Preoperative Sco2, demographics, N-terminal pro-B-type natriuretic peptide, high-sensitive troponin T, clinical outcomes, and 30-day and 1-yr mortality were recorded.Median additive EuroSCORE was 5 (range: 0–19). Thirty-day and 1-yr mortality and major morbidity (at least two major complications and/or a high-dependency unit stay of at least 10 days) were 3.5%, 7.7%, and 13.3%, respectively. Median minimal preoperative oxygen supplemented Sco2 (Sco2min-ox) was 64% (range: 15–92%). Sco2min-ox was correlated (all: P value <0.0001) with N-terminal pro-B-type natriuretic peptide (ρ: −0.35), high-sensitive troponin T (ρ: −0.28), hematocrit (ρ: 0.34), glomerular filtration rate (ρ: 0.19), EuroSCORE (τ: 0.20), and left ventricular ejection fraction class (τ: 0.12). Thirty-day nonsurvivors had a lower Sco2min-ox than survivors (median 58% [95% CI, 50.7–62%] vs. 64% [95% CI, 64–65%]; P < 0.0001). Receiver-operating curve analysis of Sco2min-ox and 30-day mortality revealed an area-under-the-curve of 0.71 (95% CI, 0.68–0.73%; P < 0.0001) in the total cohort and an area-under-the-curve of 0.77 (95% CI, 0.69–0.86%; P < 0.0001) in patients with a EuroSCORE more than 10. Logistic regression based on different EuroSCORE categories (0–2; 3–5, 6–10, >10), Sco2min-ox, and duration of cardiopulmonary bypass showed that a Sco2min-ox equal or less than 50% is an independent risk factor for 30-day and 1-yr mortality.Preoperative Sco2 levels are reflective of the severity of cardiopulmonary dysfunction, associated with short- and long-term mortality and morbidity, and may add to preoperative risk stratification in patients undergoing cardiac surgery.