Background. Thrombocytopenia is a risk factor for morbidity and mortality in critically ill patients, and is common after cardiopulmonary bypass (CPB). In this study, we evaluate whether thrombocytopenia after CPB is an independent risk factor for postoperative morbidity and mortality. Methods. We retrospectively evaluated 1364 patients requiring CPB at the University of Colorado Hospital between January 2011 and May 2016. Platelet nadir, absolute change in platelets, and percent change in platelets were modeled as continuous variables. Patients with postoperative thrombocytopenia (de fined a nadir < 75 3 10 3 / mL within 72 hours) were also compared with patients without thrombocytopenia in a propensity-matched model. The primary outcome was in-hospital mortality, and secondary outcomes included postoperative infection, postoperative acute kidney injury (AKI), postoperative stroke, and prolonged intensive care unit (ICU) and hospital lengths of stay (LOS). Results. Postoperative thrombocytopenia occurred in 356 (26.0%) patients. In multivariable analysis, platelet nadir was signi ficantly inversely associated with mortality (odds ratio [OR], 0.955; 95% con fidence interval [CI], 0.934-0.975; P < .001), postoperative infection (OR, 0.992; 95% CI, 0.986-0.999; P = .03), AKI (all stage) (OR, 0.993; 95% CI, 0.988-0.998; P [ .01), AKI (stage 3) (OR, 0.966; 95% CI, 0.951-0.982; P < .001), postoperative stroke (OR, 0.974; 95% CI, 0.956-0.992; P = .006), prolonged ICU stay (OR, 0.986; 95% CI, 0.981-0.991; P < .001), and hospital LOS (OR, 0.998; 95% CI, 0.997-0.999; P = .001). Percent change in platelets from baseline was also signi ficantly associated with all primary and secondary outcomes. Conclusions. Postoperative thrombocytopenia is independently associated with postoperative mortality, AKI, infection, stroke, and prolonged ICU and hospital LOS. Serial platelet monitoring may help identify patients at higher risk of postoperative complications. Further studies investigating strategies to reduce postoperative thrombocytopenia, including reducing CPB time, are needed. (Ann Thorac Surg 2020;110:50-7) (C) 2020 by The Society of Thoracic Surgeons