Objective Medical management with antiplatelet (AP) and statin therapy is recommended for nearly all patients undergoing vascular surgery to reduce cardiovascular events. We assessed the association between preoperative use of AP and statin medications and postoperative in-hospital myocardial infarction (MI) in patients undergoing high-risk open surgery. Methods We studied patients who underwent elective suprainguinal (n = 3039) and infrainguinal (n = 8323) bypass and open infrarenal abdominal aortic aneurysm repair (n = 3007) in the Vascular Quality Initiative (VQI, 2005-2014). We assessed the association between AP or statin use and in-hospital postoperative MI and MI/death. Multivariable logistic analyses were performed to identify the patient, procedure, and preoperative medication factors associated with postoperative MI and MI/death across procedures and patient cardiac risk strata. Secondary end points included bleeding, transfusion, and thrombotic complications. Results Most patients were taking both AP and statin preoperatively (56% both agents vs 19% AP only, 13% statin only, and 12% neither agent). Use of both agents was more common for patients in the highest cardiac risk stratum (low, 54%; intermediate, 59%; high, 61%; P <.01). Increased cardiac risk was associated with higher MI rates (1.8% vs 3.8% vs 6.5% for low, intermediate, and high risk; P <.01). By univariate analysis, MI rate was paradoxically higher for patients taking both agents (3.7%, vs statin only 2.8%, AP only 2.6%, or neither AP nor statin 2.4%; P =.003). After multivariable adjustment, rates of MI in patients taking preoperative AP only (odds ratio [OR], 0.9; 95% confidence interval [CI], 0.7-1.2) and statin only (OR, 0.8; 95% CI, 0.6-1.2) were not different from those in patients taking either or neither medication (neither agent compared with taking both agents: OR, 1.0; 95% CI, 0.7-1.4; P >.05 for all). Similarly, rates of MI/death were not associated with medication status after multivariable adjustment. Estimated blood loss >1 liter (OR, 2.4; 95% CI, 1.6-3.7; P <.01) and transfusions of 1 or 2 units (OR, 2.5; 95% CI, 2.0-3.3; P <.01) and ≥3 units (OR, 4.0; 95% CI, 3.1-5.3; P <.01) were highly associated with MI, with similar findings related to composite MI/death in multivariable analysis. Rates of blood loss were slightly higher with AP use for all procedures; however, increased transfusions occurred only for infrainguinal bypass with AP use. Rates of reoperation for bleeding, graft thrombosis, or graft revision did not differ by preoperative AP use. Conclusions Preoperative AP and statin medications as used in VQI were not associated with the rate of in-hospital MI/death after major open vascular operations. Rather, predicted cardiac risk and operative blood loss were significantly associated with in-hospital MI or MI/death. AP and statin medications appear to be more useful in reducing late mortality than early postoperative MI/death in VQI. However, they were not harmful, so their long-term benefit argues for continued use.