Objective: To discover the effects of the lowest hematocrit during cardiopulmonary bypass on end-organ function and mortality in patients who did not receive red blood cell transfusion and to identify predictors of nadir hematocrit. Methods: From November 1, 2004, to October 1, 2009, 7957 patients underwent cardiac surgery supported by cardiopulmonary bypass and were not transfused. The relationship between nadir hematocrit and morbidity, markers of end-organ function, and survival was studied using generalized propensity score analysis. Factors associated with nadir hematocrit were identified by linear regression. Results: Median nadir hematocrit was 30% (25th to 75th percentile, 27%-33%). Lower nadir hematocrit was associated with higher maximum intraoperative lactic acid (intrasubject correlation, -0.44). After risk adjustment, nadir hematocrit was associated with worse renal function (lower estimated glomerular filtration rate; P = .012), more myocardial injury (higher troponin level; P = .004), longer postoperative ventilator support (P < .001), longer hospital stay (P < .001), and higher mortality (P = .042). Female gender, older age, lower body mass index, higher New York Heart Association class, and combined valve procedure and coronary artery bypass were associated with lower nadir hematocrit; however, the strongest correlate was preoperative hematocrit (correlation coefficient, 0.74). Conclusions: Although red blood cell transfusion has associated morbidity risk, there must be a tradeoff between adverse effects of low hematocrit during cardiac surgery and those of transfusion. The strong association of nadir hematocrit with preoperative hematocrit suggests the need for investigation and optimization before elective cardiac surgery.