Objective: The purpose of this study was to investigate if the preoperative use of new platelet inhibitors and low-molecular-weight heparins may contribute to bleeding after cardiac surgery. Design: Retrospective data review. Setting: University teaching hospital. Participants: One hundred eleven patients divided in 5 groups. Interventions: Patients were grouped according to preoperative antithrombotic regimen: group 1, control, no agents (n = 55); group 2, clopidogrel (n = 9); group 3, enoxaparin (n = 17); group 4, any GP IIb/IIIa inhibitor (n = 14); and group 5, any drug combination (n = 15). Data included cumulative mediastinal chest tube drainage, allogeneic blood transfusions, total blood donor exposures, and re-exploration. Measurements and Main Results: Use of any drug (groups 2-5) resulted in greater total blood transfusions and donor exposure (p = 0.0003) than control, especially red cells (p = 0.002) and platelets (p = 0.006). A greater percentage of patients on enoxaparin required mediastinal re-exploration for nonsurgical bleeding versus control (3/17 v 0/55, p = 0.001). The use of enoxaparin was associated with significantly higher chest tube output after the first 24 hours postoperatively (p = 0.048). Conclusion: Newer antithrombotic agents were associated with greater transfusion rates and total donor exposures. Enoxaparin use was associated with greater overall blood loss and with higher incidence of mediastinal re-exploration. The relative risk-benefit ratio of reduced periprocedure morbidity versus increased bleeding complications has yet to be determined.