SummaryWe recently reported that thrombocytopenia and bleeding are often limiting effects of immunotherapy with interleukin-2 (IL-2). In order to understand the mechanisms that lead to this unexpected clinical toxicity, we studied the effects of IL-2 on in vitro platelet function. When platelet aggregation was studied using whole blood (impedance, electrical) aggregometry, inhibition of aggregation was detected within_l_min of the addition of exogenous IL-2 to whole blood. IL-2-induced platelet secretion was quantified by radioimmunoassay (RIA) of PF4, BTG, and TXB2independent of the addition of an aggregating agonist (ADP). Platelet secretion and inhibition of aggregation were an indirect consequence of a cellular effect of IL-2 on mononuclear cells, since aggregation was normal when whole blood was depleted of mononuclear cells and its reconstitution with autologous mononuclear cells led to a cell concentration- dependent inhibitory effect of aggregation and release of a-granule components in the presence of IL-2. In order to understand the mechanism of platelet secretion mediated by IL-2-activated mononuclear cells, we quantified the release of eicosanoid products from cultures of mononuclear cells exposed to IL-2 and found a significant increase in TXB2. Our results indicate that platelet secretion, indirectly initiated by IL-2-activated cells, is followed by inhibition of aggregation. These findings may not only have important implications for the planning of clinical immunotherapy trials with IL-2, but may also provide a novel link for a better understanding of the relationships between the hemostatic and the immune systems.