Abstract: There is growing evidence for an interdependence of inflammation, coagulation, and thrombosis in acute and chronic inflammatory diseases. Inflammatory bowel diseases (IBD) are associated with a hypercoagulable state and an increased risk of thromboembolism. Although the IBD-associated prothrombogenic state has been linked to the inflammatory response, the mediators that link these 2 conditions remain unclear. Recent evidence suggests that interleukin-6 (IL-6) may be important in this regard. The objective of this study was to more fully define the contribution of IL-6 to the altered platelet function that occurs during experimental colitis. The number of immature and mature platelets, activated platelets, and platelet–leukocyte aggregates were measured in wild-type and IL-6−/− mice with dextran sodium sulfate (DSS)–induced colonic inflammation. DSS treatment of WT mice was associated with significant increases in the number of both immature and mature platelets, activated platelets, and platelet–leukocyte aggregates. These platelet responses to DSS were not observed in IL-6−/− mice. Chronic IL-6 infusion (through an Alzet pump) in WT mice reproduced all of the platelet abnormalities observed in DSS-colitic mice. IL-6–infused mice also exhibited an acceleration of thrombus formation in arterioles, similar to DSS. These findings implicate IL-6 in the platelet activation and enhanced platelet–leukocyte aggregate formation associated with experimental colitis, and support a role for this cytokine as a mediator of the enhanced thrombogenesis in IBD.