Platelets have important roles in the development of venous thromboembolism (VTE). In experimental studies, including animal models of venous thrombosis, platelets were found to augment thrombus formation, for example, via recruitment of leukocytes and the importance of the interactions between platelets and the plasmatic coagulation system for the development of VTE has been demonstrated. Furthermore, studies on patients with acute VTE and on patients at high risk for VTE have revealed that markers of platelet activation are elevated in these settings. Specifically, platelet markers, such as soluble P-selectin, might serve as biomarkers for acute VTE or to identify patients with a high risk of VTE. Most convincingly, anti-platelet therapy with aspirin has been found to reduce the risk of VTE after orthopedic surgery and has demonstrated similar efficacy to anticoagulant drugs in this context. Aspirin also reduces the risk of recurrent VTE after a first event, although in this setting anticoagulation remains the most effective treatment option. The therapeutic effect of aspirin in the prevention of VTE proves the concept that platelets are important players in thrombosis of the venous system.