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Background: Epidemiologic studies have shown that there is an association between acute respiratory infection and acute coronary syndrome. The aim of this study was to analyze the thrombotic risk, assessed by platelet aggregation and aspirin non-responsiveness, in patients with an acute coronary syndrome complicated by an infection. Methods: Patients with an acute coronary syndrome who were admitted to the intensive care unit and hospitalized for at least 3 days in 2002 and 2003 were eligible for the study. Three hundred and fifty-eight patients were included, of whom 66 had an infection during their hospital stay. Platelet aggregation was analyzed by an aggregometer using laser light (PA-200, laser light scattering). Aspirin non-responsiveness was defined as a closure time of ≤193 s measured by PFA-100. Results: Platelet aggregation was more pronounced during an infectious complication (P < 0.001). The subgroups of patients with persistent fever, urinary tract infection, and pneumonia all had a higher level of aggregates than the group of patients without an infection (P = 0.007, P = 0.04, and P = 0.01, respectively). Aspirin non-responsiveness was more frequent in the group of subjects with pneumonia compared with those without an infection, 90% vs. 46% (P = 0.006). The CRP levels were independently associated with platelet aggregation and aspirin non-responsiveness (P < 0.001, P < 0.001, respectively). Conclusion: An infectious complication during the course of an acute coronary syndrome leads to more pronounced platelet aggregation. Aspirin non-responsiveness is more frequent in severe infections, such as pneumonia. CRP is an independent predictor of platelet aggregation and aspirin non-responsiveness in the setting of an acute coronary syndrome.