BackgroundThere is still uncertainty about the safety of aprotinin for coronary artery bypass graft surgery. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral versus single internal thoracic artery grafting. Many of theARTpatients (≈30%) received perioperative aprotinin. We investigated the association between perioperative aprotinin administration and short‐term (in‐hospital) and long‐term outcomes by performing a post hoc analysis of theART.Methods and ResultsAmong patients enrolled in theART(n=3102) from 2004 to 2007, we excluded those who did not undergo surgery (n=18) and those with no information about use of perioperative aprotinin (n=9). Finally, 836 of 3076 patients (27%) received aprotinin. Propensity matching was used to select 536 pairs for final comparison. Aprotinin was also associated with an increased risk of hospital mortality (9 [1.7%] versus 1 [0.2%]; odds ratio, 9.12; 95% confidence interval [CI], 1.15–72.2;P=0.03), intra‐aortic balloon pump insertion (37 [6.9%] versus 17 [3.2%]; odds ratio, 2.26; 95%CI, 1.26–4.07;P=0.006), and acute kidney injury (102 [19.0%] versus 76 [14.2%]; odds ratio, 1.42; 95%CI, 1.03–1.97;P=0.03). Aprotinin was not associated with a lower incidence of transfusion (37 [6.9%] versus 28 [5.2%]; odds ratio, 1.34; 95%CI, 0.81–2.23;P=0.25) and reexploration (26 [4.9%] versus 19 [3.5%]; hazard ratio, 1.39; 95%CI, 0.76–2.53;P=0.28). At 5 years, all‐cause mortality was significantly increased in the aprotinin group (56 [10.6%] versus 38 [7.3%]; hazard ratio, 1.51; 95%CI, 1.0–2.28;P=0.045).ConclusionsIn the present post hocARTanalysis, aprotinin was associated with a significantly increased risk of early and late mortality.Clinical Trial RegistrationURL:http://www.isrctn.com. Unique identifier:ISRCTN46552265.