Background Cerebral hyperperfusion syndrome (CHS), characterized by severe ipsilateral headache, seizures, and intracranial hemorrhage, is a rare, poorly understood complication that can be fatal following carotid endarterectomy (CEA). The purpose of the study was to determine the factors associated with CHS as captured in the Vascular Quality Initiative. Methods Analysis was conducted on 51,001 procedures captured from the CEA module of the Vascular Quality Initiative from 2003 to 2015. Preoperative, operative, and postoperative variables were considered for inclusion in logistic regression analyses to determine possible associations with CHS. The relative contribution of each variable to the overall model was determined using dominance analysis. Results The mean age was 70.2 ± 9.4 years; there were 39.6% female patients, 93.1% of white race, with 29.6% of CEAs being performed for symptomatic status. The overall rate of CHS was 0.18% (n = 94), with 55.1% occurring in asymptomatic and 44.9% occurring in symptomatic patients with an associated mortality rate of 38.2%. Multivariable analysis including preoperative variables showed that female gender (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.09-2.51; P = .019), <1 month major ipsilateral stroke (OR, 5.36; 95% CI, 2.35-12.22; P < .001), coronary artery disease (OR, 1.77; 95% CI, 1.15-2.71; P = .009), and contralateral stenosis ≥70% (OR, 1.54; 95% CI, 1.00-2.36; P = .050) were independently associated with CHS and that <1 month major stroke was the most important contributor to the model. With the additional inclusion of operative and postoperative variables, female gender (OR, 1.75; 95% CI, 1.14-2.67; P = .010), <1 month ipsilateral major stroke (OR, 3.20; 95% CI, 1.32-7.74; P = .010), urgency (OR, 2.25; 95% CI, 1.38-3.67; P = .001), re-exploration (OR, 2.98; 95% CI, 1.27-6.97; P = .012), postoperative hypertension (OR, 4.09; 95% CI, 2.65-6.32; P < .001), postoperative hypotension (OR, 3.21; 95% CI, 1.97-5.24; P < .001), dysrhythmias (OR, 3.23; 95% CI, 1.64-6.38; P = .001), and postoperative myocardial infarction (OR, 2.84; 95% CI, 1.21-6.67; P = .017) were significantly associated with CHS, with postoperative blood pressure lability and cardiac complications having the strongest associations with CHS. Conclusions The risk of CHS was highest in female patients and in those with a recent major stroke, coronary artery disease, and contralateral stenosis ≥70%. In addition, in adjusting for operative and postoperative variables, CHS was most significantly associated with postoperative blood pressure lability and cardiac complications. These data lend insight into a high-risk population for this devastating complication.