Certain drug therapies, such as heparin, warfarin, and aspirin, are associated with prothrombotic or hypercoagulable states. If these agents that are administered to prevent thrombosis have been associated with its opposite effect, then agents that are specifically given to inhibit bleeding may produce a deleterious hypocoagulable effect. This article evaluates the risks presented by serine protease inhibitors (ie, aprotinin), lysine analog antifibrinolyics (ie, epsilon aminocaproic acid [Amicar, Wyeth-Ayerst, Philadelphia, PA] and tranexamic acid), and desmopressin acetate (DDAVP, Rhone-Poulenc Rorer, Collegeville, PA). It focuses on their mechanisms of action, particularly their effect on microvascular tone and endothelial function, coagulation factors, platelet function, and the fibrinolytic pathway. It discusses their use in the presence of known thrombin production or fibrinogen conversion and whether certain vascular beds are more prone to drug-related thrombosis.