Background Metabolic syndrome (MS) is associated with a prothrombotic state and predicts the subsequent development of type 2 diabetes mellitus. We hypothesized that similar to diabetes, subjects with MS may have increased platelet reactivity, and reduced response to aspirin. We, therefore, compared platelet reactivity and response to aspirin among subjects with MS and healthy volunteers. Methods Fifty subjects with MS, defined by Adult Treatment Panel III criteria (age 44 ± 9 years, 80% women, body mass index 35 ± 8 kg/m 2) were compared to 50 healthy controls who met none of the MS criteria (age 40 ± 7 years, 80% women, body mass index: 24 ± 3 kg/m 2). Blood samples were taken before and 24 hours after 325 mg aspirin (single dose). Platelet function was evaluated by aggregation in response to 1.5 mmol/L arachidonic acid, 1 μg/mL collagen, and 5 and 20 μmol/L adenosine diphosphate; the VerifyNow Aspirin assay (Accumetrics Inc, San Diego, CA); Impact-R Cone and Plate(let) Analyzer (shear-dependent test) (DiaMed, Cresier, Switzerland) and flow cytometric determination of P-selectin expression and activated glycoprotein IIb/IIIa expression; and reticulated platelets (reflecting platelet turnover). Results Subjects with MS had higher baseline P-selectin levels (14.5 ± 5 vs 11.3 ± 4 mean fluorescence intensity, P = .002), reticulated platelets (2.8% ± 3% vs 1.2% ± 1%, P = .04) and platelet deposition under flow (Impact-R 7.5% ± 2% vs 5.9% ± 2%, P = .003). Subjects with MS also had lower response to aspirin, as evaluated by the change in all platelet aggregation assays and the VerifyNow score. Conclusions Subjects with MS appear to have increased baseline platelet reactivity and turnover and a lower antiplatelet response to aspirin. Further research is required to elucidate platelet properties in subjects with MS and find ways to modify them.