Previous studies have explored the association between hemorheologic alterations and aspirin resistance, pointing out the possible interaction between hematologic components and platelet responsiveness to antiplatelet drugs. The aim of this study was to evaluate the association between hemorheologic variables and residual platelet reactivity in patients with acute coronary syndromes (ACSs) who underwent percutaneous coronary intervention on dual antiplatelet therapy. The study population included 528 patients with ACSs. Hemorheologic studies were performed by assessing whole blood viscosity at 0.512 and 94.5/second, plasma viscosity, and erythrocyte deformability index. Post-treatment platelet reactivity was investigated by measuring platelet aggregation by adenosine 5'-diphosphate (ADP) 10 mumol and a value >70% was defined as high ADP platelet reactivity. Significantly (p <0.01) lower values of hematocrit and erythrocyte deformability and higher values of whole blood viscosity at 94.5/second were found in patients with high ADP platelet reactivity. At multivariate analysis, lower values of hematocrit and erythrocyte deformability index and higher values of whole blood viscosity at 94.5/second and leukocytes (highest vs lowest tertile) also resulted in an independent association with high platelet reactivity, except for leukocytes, after simultaneous adjustment for hematocrit, leukocyte count, and erythrocyte deformability index. In conclusion, these results demonstrate the influence of hematocrit and of erythrocyte deformability on ADP platelet reactivity. These variables could be considered to optimize treatment with antiplatelet therapy in these patients.