Increased hemodilution severity during cardiopulmonary bypass was associated with worse perioperative vital organ dysfunction/morbidity and increased resource use, as well as greater short- and intermediate-term mortality. We speculate that these results derive from inadequate oxygen delivery causing ischemic and/or inflammatory vital organ injury, as recently demonstrated intravitally in cerebral tissues. Although this analysis of a large observational study offers evidence linking low on-pump hematocrit values to these adverse outcomes, prospective randomized trials are needed (1) to establish whether a causal effect of hemodilution on poor outcomes actually exists and (2) to test the potential efficacy of maintaining on-pump hematocrit above 22% for improving outcomes of cardiopulmonary bypass.