Objective The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) demonstrated a higher periprocedural stroke and death (S+D) rate among patients randomized to carotid artery stenting (CAS) than to carotid endarterectomy (CEA). Herein, we seek factors that affect the CAS-CEA treatment differences and potentially to identify a subgroup of patients for whom CAS and CEA have equivalent periprocedural S+D risk. Methods Patient and arterial characteristics were assessed as effect modifiers of the CAS-CEA treatment difference in 2502 patients by the addition of factor-by-treatment interaction terms to a logistic regression model. Results Lesion length and lesions that were contiguous or were sequential and noncontiguous extending remote from the bulb were identified as influencing the CAS-to-CEA S+D treatment difference. For those with longer lesion length (≥12.85 mm), the risk of CAS was higher than that of CEA (odds ratio [OR], 3.42; 95% confidence interval [CI], 1.19-9.78). Among patients with sequential or remote lesions extending beyond the bulb, the risk for S+D was higher for CAS relative to CEA (OR, 9.01; 95% CI, 1.20-67.8). For the 37% of patients with lesions that were both short and contiguous, the odds of S+D in those treated with CAS was nonsignificantly 28% lower than for CEA (OR, 0.72; 95% CI, 0.21-2.46). Conclusions The higher S+D risk for those treated with CAS appears to be largely isolated to those with longer lesion length and/or those with sequential and remote lesions. In the absence of those lesion characteristics, CAS appears to be as safe as CEA with regard to periprocedural risk of S+D.