The basis for many febrile nonhemolytic transfusion reactions associated with platelet transfusion therapy is cytokine elaboration and accumulation in the storage bag, which correlate with the leukocyte content and the length of platelet storage. We propose that a possible additional variable in the elaboration and accumulation of cytokines is the differential adhesion of mononuclear cells to the plastic substrate of the platelet storage bag. We hypothesize that mononuclear cell adhesion-induced cytokine release is greater in random-donor platelet bags composed of the polyolefin polymer compared to the single-donor apheresis platelet bags composed of the polyvinyl chloride polymer with the tri-(2-ethylhexyl) trimellitate (TEHTM) plasticizer. For four blood donors, we demonstrate preferential mononuclear cell adhesion, in vitro, to discs of polyolefin polymer versus discs of polyvinyl chloride polymer with the TEHTM plasticizer. Scanning electron microscopy corroborates this. In addition, proinflammatory cytokine (interleukin 1 [IL-1] and tumor necrosis factor alpha [TNF-]) levels are greater in culture wells containing discs of polyolefin polymer than in those containing discs of polyvinyl chloride polymer with the TEHTM plasticizer, and even more so in storage bags containing polyolefin polymer versus polyvinyl chloride polymer with the TEHTM plasticizer (IL-1, TNF-, IL-6, and IL-8). This study suggests, for the first time, that differential plastic substrate mononuclear cell adhesion may contribute to cytokine release during platelet storage. This may represent an additional variable in the pathophysiology of febrile nonhemolytic transfusion reactions in patients receiving stored platelet units.