Aprotinin reduces bleeding and transfusion rates in patients undergoing coronary surgery while on clopidogrel. However, safety studies have indicated that aprotinin may have a possible adverse effect related to an increased incidence of thromboembolic events. We therefore studied the adenosinediphosphate (ADP) mediated platelet aggregation before and after administration of aprotinin in patients on clopidogrel. Fifteen clopidogrel-treated patients with acute coronary syndrome undergoing coronary surgery were studied. ADP-mediated platelet aggregation and platelet count ratio (%) were measured before and after a bolus dose [2 x 10(6) kallikrein inhibiting units (KIU)] of aprotinin. Aprotinin induced an increased aggregation in 11 of 15 patients (73%), and a decrease was registered in two patients (13%). The median (25th/75th percentile) ADP-mediated platelet aggregation before and after aprotinin was 84% (76/91) and 94% (86/97, P<0.01). Clopidogrel non-responders with >90% aggregation (n=4) had a median aggregation of 94.5% (91.5/97.5) vs. 82% (73/87, P<0.01) in the responders (n=11). The median increase in platelet aggregation after aprotinin was 8% (5/20) in the responders vs. 0% (-5.25/3, P<0.01) in the non-responders. Aprotinin increased ADP induced platelet aggregation from 84 to 94% in patients on clopidogrel, which corresponds to a median decrease in relative platelet inhibition of >50%.