The aim of our study was to investigate the combined in vitro effects of melagatran and eptifibatide on platelet aggregation and thrombin generation under low and high coagulant challenge in tissue-factor-activated, platelet-rich plasma. Increasing amounts of melagatran dose-dependently decreased prothrombin fragment 1.2 and activated factor X values, and dose-dependently prolonged the lag phase until the onset of platelet aggregation. Eptifibatide exerted a dose-dependent anti-aggregating effect under both high and low coagulant challenge. The combination of melagatran and eptifibatide resulted in significant additive prolongation of the lag phase until the onset of platelet aggregation, which was more pronounced under low coagulant challenge. Under low, but not under high, coagulant challenge, the combination of melagatran and eptifibatide had a significant additive inhibitory effect on platelet aggregation. No additive effects on decreasing prothrombin fragment 1.2 and activated factor X values were observed with combined administration of the drugs. The present study demonstrates the additive effect of melagatran and eptifibatide on platelet aggregation inhibition and on prolongation of the lag phase until the onset of platelet aggregation.