We report here that soluble CD40 ligand (sCD40L) is released from human platelets when activated with collagen or thrombin. The sCD40L was detectable in the culture supernatants of platelets within 30 min after stimulation in vitro, and reached maximal levels in 3 h. The release was blocked by the metalloproteinase inhibitor, KB8301, indicating that the soluble CD40L is made by cleaving the membrane bound CD40L expressed on activated platelets. The sCD40L was undetectable in the supernatant of the activated platelets obtained from patients with X-linked hyper IgM syndrome (XHIM), who have defects in CD40L gene. Since sCD40L has been shown to have biologic function on the activation of vascular endothelial cells and B cells, these findings suggest that platelets play some roles in both inflammation and humoral immune response by releasing soluble CD40L.