Chronic inflammation is a poorly understood, but problematic, manisfestation of sickle cell disease (SCD). The potent inflammatory mediator CD40L increases leukocyte proliferation, endothelial adhesiveness and procoagulant activity once it is exposed and released from encrypted sites following platelet activation. Since elevated leukocyte counts, adhesion and coagulation are associated with more clinically severe courses of SCD along with platelets that are more activated than normal, platelet CD40L is hypothesized to be an important mediator of inflammation in SCD. Data shown here indicate that CD40L is thirty-fold higher in SCD plasma but significantly reduced in SCD platelets. SCD plasma induces B cell proliferation, endothelial activation and procoagulant tissue factor production, all in a manner partially dependent on recognition of CD40L. When CD40L activity was blocked in a mouse model of SCD, lung, liver and kidney pathology was demonstrably reduced. More dramatically, anti-CD40L treatment of SCD mice prevented the architectural disruption and drastic enlargement of the spleen that is characteristic of SCD. These data suggest that functional CD40L is available and likely mediates inflammation in SCD. Furthermore, in a phase I clinical trial, the αIIbβ3 antagonist eptifibatide reduced plasma CD40L, favorably altered the inflammatory cytokine profile of SCD plasma and was well-tolerated by SCD patients. This study provides the first evidence that inflammation and organ pathology in SCD are mediated by plateletderived CD40L. Since plasma CD40L can be safely reduced by anti-platelet medication, we identify both CD40L and platelets as potential therapeutic targets to treat SCD.