High aggregatory responses despite antiplatelet treatment is associated with an increased risk of thrombotic complications following percutaneous coronary intervention (PCI). In the present study, we investigated the relationship between platelet aggregatory responses to ADP and the release of CD40L (sCD40L): an immunomodulatory compound involved in atherothrombosis - in patients undergoing PCI. ADP-induced platelet aggregation, sCD40L and soluble P-selectin (sP-selectin) were determined before and 24 h after PCI, in samples from 52 patients receiving aspirin and thienopyridines. Platelet aggregation to ADP above the median was defined as 'high aggregation', and aggregation below the median as 'low aggregation'. Data below are medians and interquartile ranges. Patients with 'high platelet aggregability' had a significantly higher increase in both sCD40L (Delta-values: 0.78 (-0.19-3.18) vs. -0.65 (-2.10-0.00) ng/ml, P = 0.002) and sP-selectin (Delta-values: 8.0 (-2.00-16.00) vs. 4.50 (-13.00-0.50) ng/ml, P = 0.001) compared with patients with 'low platelet aggregability'. In a multivariate linear regression analysis adjusted for clinical characteristics and type of preintervention therapy, the only independent predictors of sCD40L and sP-selectin were platelet aggregation to ADP before PCI (P < 0.001) and the combination of platelet aggregation to ADP before PCI and urgency of PCI (P < 0.001). Circulating CD40L is more markedly increased after PCI in patients with high ADP-induced platelet aggregation.