Bivalirudin, a synthetic analog of the carboxy-terminus of hirudin, is a reversible thrombin inhibitor used during coronary balloon angioplasty. The objective of this study was to evaluate the influence of bivalirudin on thrombin generation. Three in-vitro models (numerical simulations, synthetic coagulation proteome and whole blood) of contact pathway-independent blood coagulation triggered with tissue factor were used in this study. Increasing concentrations of bivalirudin prolong the initiation phase of thrombin generation in a concentration-dependent manner. At subpharmacologic bivalirudin concentrations (0.5–2 μmol/l), total thrombin generation was significantly increased. At a pharmacologic concentration (5 μmol/l), bivalirudin suppressed thrombin generation in the synthetic coagulation proteome; in numerical simulations and contact pathway-inhibited whole blood, no thrombin generation was detected over 1200–2000 s and platelet activation was inhibited by 80%. The addition of a pharmacologic concentration (9 μmol/l) of a naturally occurring protease inhibitor aprotinin in the presence of at least 0.5 μmol/l bivalirudin provided limited enhancement of the bivalirudin inhibitory effect. In conclusion, bivalirudin at pharmacologic concentrations is an efficient inhibitor of thrombin generation, platelet activation and clot formation, which acts not as a modulator but as an ‘on–off’ switch of blood coagulation.