Up to 20% of serious vascular events in high-risk vascular patients is attributable to a failure of aspirin (ASA) to suppress platelet aggregation. Resveratrol is a cardioprotective phytoestrogen that can inhibit platelet aggregation in animal models. We hypothesized that resveratrol can also inhibit aggregation of platelets from ASA-resistant (ASA-R) patients. Thus, platelet-rich plasma was isolated from ASA-sensitive (ASA-S) and ASA-R patients (aspirin resistance was defined as higher-than-expected aggregation to collagen and epinephrine [>/=40%] after oral treatment with 100 mg/d ASA). Aggregation to adenosine diphosphate (ADP; 5 and 10 mumol/L), collagen (2 mug/mL), and epinephrine (10 mumol/L) in the absence and presence of resveratrol (10 mol/L) was measured by optical aggregometry. Maximal aggregation to 5 mumol/L ADP was only slightly affected by resveratrol. Similar results were obtained using 10 mumol/L ADP. Maximal aggregation of ASA-R platelets to collagen was significantly decreased by resveratrol, whereas resveratrol had only marginal effects in ASA-S platelets. Similar results were obtained with epinephrine as well. Collectively, resveratrol effectively inhibited collagen- and epinephrine-induced aggregation of platelets from ASA-R patients, which may contribute to its cardioprotective effects in high-risk cardiac patients.