In order to further characterize the modulation of the ADP-induced aggregation of gel-filtered human platelets by beta 2-glycoprotein-I (beta 2-G-I), the influence of this glycoprotein upon the serotonin (5-HT) release during aggregation was measured. The following results were obtained: beta 2-G-I completely inhibits the 5-HT release during ADP-induced platelet activation. The inhibition is correlated with the inhibition of the second wave of the ADP-induced aggregation. This effect of beta 2-G-I is not dose-dependent and appears above a threshold concentration of 0.1-0.15 mg/ml in the assay. The specificity of the beta 2-G-I interaction with the ADP-activation is supported by results obtained with collagen or thrombin as aggregating agents. In these cases neither the aggregation nor the release is influenced by the glycoprotein. In respect to the results obtained, beta 2-G-I is a potent candidate to be a modulator of ADP-induced platelet activation in vivo.