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Controversy persists surrounding the perceived bleeding risk associated with perioperative clopidogrel use in patients undergoing lower extremity bypass (LEB). The purpose of this study was to examine the LEB bleeding risk and clinical sequelae associated with clopidogrel.All LEBs in the Vascular Quality Initiative (VQI) from 2008 to 2014 were studied. The exposure was perioperative clopidogrel. Primary outcomes were blood transfusion, estimated blood loss ≥500 mL, and reoperation for bleeding. Secondary outcomes included mean operative time, major cardiac events, respiratory complications, infectious complications, and in-hospital mortality. Univariate and multivariable analyses were used to analyze patients on the basis of clopidogrel use and its association with outcomes. Nonparametric test for trend and Mantel-Haenszel methods were used to analyze association of clopidogrel use with blood transfusion and secondary outcomes.Among the LEB cohort (N = 9179), 28% (n = 2544) were taking clopidogrel and 72% (n = 6635) were not. Patients taking clopidogrel were more likely to have coronary disease, prior coronary intervention, abnormal findings on stress test, and aspirin use (P < .001 for all). Patients taking clopidogrel were more likely to receive blood transfusion (38% vs 24%; P < .001) and to have estimated blood loss ≥500 mL (21% vs 12%; P < .001). Reoperation for bleeding rates were similar (0.9% vs 1.1%; P = .9). Clopidogrel use was also associated with increased mean operative times (244 minutes vs 232 minutes; P < .001) as well as with cardiac complications (8.8% vs 6.5%; P = .001), respiratory complications (2.5% vs 1.6%; P = .007), and in-hospital mortality (1.3% vs 0.8%; P = .03). Multivariable analysis demonstrated that clopidogrel was associated with increased risk of 1- or 2-unit blood transfusion (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.5-2.1; P < .001) and >2-unit blood transfusion (OR, 2.0; 95% CI, 1.7-2.5; P < .001). Major cardiac events (OR, 1.2; 95% CI, 1.0-1.5; P = .05) and respiratory complications (OR, 1.4; 95% CI, 1.0-2.0; P = .03) were also independently associated with clopidogrel use. Weighted Mantel-Haenszel ORs controlling for blood transfusion amount revealed no remaining effect of clopidogrel on major cardiac events (OR, 1.1; P = .4) or respiratory complications (OR, 1.0; P = .8).Perioperative clopidogrel use in LEB surgery is associated with increased blood loss and blood transfusion. Associated clinical sequelae include increased cardiac and pulmonary complications. Accordingly, surgeons should consider discontinuation of perioperative clopidogrel when it is clinically appropriate unless it is strongly indicated at the time of LEB.