Background: The objectives of this study are to determine the effect of heparin-induced thrombocytopenia (HIT) on postoperative morbidity and mortality after cardiac surgery and to identify preoperative risk factors for HIT. Methods: From 2002 to 2005, 487 cardiac surgery patients with postoperative thrombocytopenia (50% drop in platelet count or absolute count < 100,000/μL) underwent at least one enzyme-linked immunosorbent assay for HIT platelet factor 4 antibodies. Risk factors and outcomes of patients with a positive HIT assay (HIT+) were compared with patients with thrombocytopenia, but without HIT antibodies (HIT-). Results: 23.2% of patients (113 of 487) were HIT+. Multivariable predictors of HIT included previous percutaneous coronary interventions (odds ratio [OR] = 1.76, p = 0.03), class IV New York Heart Association heart failure (OR = 1.80, p = 0.012), and infectious endocarditis (OR = 3.66, p = 0.0123). Postoperative infections occurred more frequently in HIT+ patients, including sepsis (16.8% versus 9.9%, p = 0.0433) and pneumonia (46.9% versus 23.3 %, p < 0.001). The HIT+ patients also had a higher rate of renal failure requiring hemodialysis (23.0% versus 9.1%, p < 0.001) and acute limb ischemia (15.9% versus 4.3%, p < 0.001). Thirty-day mortality was significantly higher in the HIT+ group (24.8% versus 15.2%, p = 0.019). Postoperative HIT emerged as an independent predictor of renal failure (OR = 1.73, p < 0.001) and thromboembolic complications (OR = 2.39, p = 0.02). Conclusions: Heparin-induced thrombocytopenia patients are at significantly greater risk of thrombosis, renal failure, and mortality in the postoperative setting. Greater awareness of this devastating problem may allow earlier detection of HIT, with prompt institution of appropriate anticoagulation therapy, which could potentially limit the associated morbidity and mortality.