Objective To investigate the predictive role of systemic immune-inflammation index (SII) on postoperative poor outcome in patients undergoing carotid endarterectomy (CEA). Methods A total of 347 patients undergoing elective isolated CEA between March 2010 and April 2022 were included in this multicenter retrospective observational cohort and risk-prediction study and were divided into two groups as poor outcome group ( n = 23) and favorable outcome group ( n = 324). Poor outcome was defined as the presence of at least one of the complications within 30 days of surgery including stroke, myocardial infarction, and death. The patients' baseline clinical characteristics, comorbidities, and hematological indices were derived from the complete blood count (CBC) analysis, and perioperative data, outcomes, and complications were screened, recorded, and then compared between the groups. Multivariate logistic regression and receiver-operating characteristic (ROC) curve analyses were conducted following univariate analyses to detect the independent predictors of poor outcome as well as the cutoff values with sensitivity and specificity rates. Results A total of 23 patients out of 347 (6.6%) manifested poor outcome; and stroke, myocardial infarction, and death occurred in 13, 3, and 7 cases, respectively. There were no significant differences between the groups in terms of basic clinical characteristics, comorbidities, and perioperative data, except for lengths of intensive care unit and hospital stays. Although the median values of PLT, PLR, NLR, and SII of the poor outcome group were found to be significantly higher than the favorable outcome group in univariate analysis, only SII was detected to be a significant and independent predictor of poor outcome in multivariate logistic regression analysis (OR = 1.0008; 95% CI: 1.0004–1.0012; p = 0.002). ROC curve analysis revealed that SII of 1356 × 103/mm3 constituted the cutoff value for predicting poor outcome with 78.3% sensitivity and 64.5% specificity (AUC = 0.746; 95% CI: 0.64–0.851). Conclusions Our study revealed for the first time in the literature that SII significantly predicted poor outcome after CEA.