Background An antiplatelet therapy with acetylsalicylic acid (ASA) is prescribed in the prevention of cardiovascular events, but around 24% of ASA takers are resistant to the treatment. Aim In this prospective, observational cohort study, we aimed to identify the prevalence and risk factors of ASA nonresponse in patients who underwent vascular surgery. Methods The study was conducted in the University hospital in Frankfurt am Main. In total, 70 patients were pre-treated with 100 mg of ASA per day and underwent either elective carotid thromboendarterectomy, femoral thromboendarterectomy or endovascular aneurysm repair of the abdominal aorta. The platelet function was measured on the first preoperative and the second or fourth postoperative day with the multiple electrode aggregometry by in-vitro stimulation with arachidonic acid (ASPItest) and thrombin receptor activating peptide 6 (TRAPtest). The primary end point was the in-vitro induced platelet aggregation in the ASPItest. If the ASPItest amounted ≥400 AU × min, the patients were categorized as ASA nonresponders. Results The total prevalence of ASA nonresponse in our study was 20% preoperatively and 35.7% postoperatively (p = 0.005). As significant predictors for ASA nonresponse, we demonstrated the area under the aggregation curve in the TRAPtest preoperatively (p = 0.04) and postoperatively (p = 0.02), and the two comorbidities arterial hypertension ( P < .001; rho 0.44) and diabetes mellitus (p = 0.04; rho 0.39), which are already well known to be associated with ASA nonresponse. Conclusion In conclusion, data of the study indicate a high incidence of perioperative, laboratory ASA nonresponse in patients undergoing vascular surgery.