The danger model of immunity and tolerance holds that antigen-presenting cells (APCs), activated by stress, injury, or necrosis, but not by physiological (apoptotic) cell death, initiate adaptive immune responses. APC activation is fundamentally associated with binding of CD40 to its ligand CD154. Platelets express CD154 upon activation and are thus potential primal danger signals linking the homeostatic response to trauma to activation of the acquired immune system. Previously, we showed that platelets can undergo gradient-driven migration, or chemotaxis, toward supernatants from cells injured by repeated freeze/thaws, UV light, or ischemia/reperfusion. Herein, we demonstrate that platelet-derived CD154 induces immature dendritic cell maturation with upregulation of costimulatory molecules and IL-12p40 production. Overall, these results provide a mechanism for platelet activation of APC facilitating the induction of adaptive immunity in environments of cell injury.