Concomitant antithrombotic therapy is essential for the prevention of ischaemic events in percutaneous coronary intervention (PCI) and stenting. With new anticoagulant medications being developed and applied in PCI, this raises the question of possible interactions with platelet and leukocyte activation. We therefore sought to investigate the influence of bivalirudin and heparin in platelet and leukocyte activation in patients undergoing elective PCI. Forty-six patients were recruited consecutively in the setting of the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT)-3 trial and were randomly assigned to receive either unfactionated heparin or bivalirudin during elective PCI. Surface expression of CD62P (P-Selectin), CD42b (GPIbalpha), CD40L, PAC-1 on circulating platelets and CD11b, CD14 and CD15 on circulating leukocytes were evaluated by flow cytometry. Cytokine levels of IL-12p70, tumour necrosis factor (TNF), IL-8, IL-6, IL-1beta and IL-10 were determined by cytometric bead array. Platelet surface expression of PAC-1, P-Selectin and GPIbalpha was significantly reduced after PCI in patients receiving bivalirudin as compared to heparin. Similarly, CD11b expression on CD14+ monocytes was diminished after bivalirudin. However, no differences were observed in cytokine levels between the bivalirudin and the heparin group, before or after PCI. In conclusion, our data suggest that bivalirudin may reduce platelet and monocyte activation in patients undergoing elective PCI. Thereby, bivalirudin might reduce periinterventional thrombotic complications.