Background: A discrepancy between characteristics of patients treated with carotid angioplasty and stent placement (CAS) within and outside clinical trials, particularly characteristics with direct impact on clinical outcome, may limit generalization of clinical trial results. The objective of this study was to identify differences in demographic and clinical characteristics and outcomes related to CAS in patients treated within clinical trials and those treated outside clinical trials in a large national cohort. Methods: We determined the frequency of CAS performed within and outside clinical trials and associated in-hospital outcomes using data from the Nationwide Inpatient Survey data files from 2005 to 2009. All the in-hospital outcomes were analyzed after adjusting for potential confounders using multivariate analysis. Results: Of the 81,638 patients who underwent CAS, 16,078 (19.6%) underwent the procedure as part of a clinical trial. The mean age of the patients was significantly lower in patients treated with CAS as part of a clinical trial than those treated with CAS outside a clinical trial. The proportion of women and nonwhites was lower among patients treated with CAS as part of a clinical trial. The in-hospital mortality was two-fold higher among patients treated with CAS outside clinical trials (1.12% vs 0.53%; P =.0005). The rate of composite endpoint of stroke, cardiac events, and death was significantly higher among patients treated with CAS outside clinical trials (P =.02). After adjusting for age, gender, presence of renal failure, and hospital bed size, CAS performed as part of a clinical trial was associated with lower rates of in-hospital mortality (odds ratio, 0.467; 95% confidence interval, 0.290-0.751; P =.0017) and composite endpoint of stroke, cardiac events, and death (odds ratio, 0.752; 95% confidence interval, 0.594-0.952; P =.0180). Conclusions: Our results suggest that CAS procedures performed as part of clinical trials was associated with lower rates of in-hospital mortality and composite endpoint of stroke, cardiac events, and death in United States. These findings highlight the need for strategies that ensure appropriate adoption of CAS to ensure that the benefits observed in clinical trials can be replicated in general practice.