Recent studies have focused on the accumulation of cytokines in stored platelet concentrates and the role that these cytokines play in mediating transfusion reactions. To elucidate any additional adverse effects that may be associated with cytokine accumulation, the authors examined whether cytokines, which normally accumulate during routine platelet storage, can cause platelet activation in vitro. Concentrations of IL-6 and IL-8 were first determined for random donor platelet concentrates on days 1 through 4 of storage. Fresh platelets were then incubated with these levels of exogenous cytokines, and activation measured by flow cytometry using a monoclonal antibody directed against p-Selectin. Significant platelet activation was observed with concentrations of cytokines which are normally present in days 3 and 4 of shelf life. The study data demonstrate that levels of cytokines that routinely accumulate in stored platelet products can affect platelet biology. Strategies to reduce cytokine generation during platelet storage may be a method to improve the function and viability of stored platelets used for transfusion.