Background: Transcatheter aortic valve replacement (TAVR) has become the dominant treatment for aortic valve disease. While TAVR safety has improved over time, concern remains over the occurrence of cerebrovascular accidents (CVA) secondary to device placement, which is associated with increased morbidity and mortality. The Sentinel Cerebral Protection System (CPS) was developed to reduce the risk of embolic strokes associated with debris produced during TAVR. Studies evaluating Sentinel CPS efficacy have produced conflicting results, and there is little understanding of which patients are selected for device placement in “real-world” settings. With no existing guidelines on device use, the purpose of this study was to describe and compare the characteristics of patients who receive CPS with those who do not in a “real-world” setting of consecutive TAVR patients and evaluate its impact on postoperative complications, namely stroke. Methods: This was a single-center, retrospective study of all patients undergoing TAVR between July 1, 2019, and December 31, 2020. Patient demographics, baseline, and perioperative characteristics were collected prospectively using the Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) Registry and our institution’s TAVR database for analysis. Postoperative outcomes were assessed using primary endpoints of in-hospital/30-day stroke and the composite of death, stroke, and bleeding/vascular events at one-year. To adjust for baseline differences, a propensity score was developed including all factors that were different between groups, and Multivariate Cox Regression analysis was used to control for these differences. Patient follow-up was 97% complete at 12 months with 100% echocardiographic follow-up. Results: A total of 242 consecutive patients (57.9% male) were analyzed, with a mean age of 79.9 \pm 9 years. Of these patients, 134 (55.4%) received the Sentinel CPS and 108 (44.6%) did not. Sentinel CPS patients were more likely to be male, not on dialysis, without prior CVA or pacemaker, had less severe chronic lung disease, and were lower operative risk compared to concurrent non-CPS patients. CPS patients were also found to have higher hemoglobin and albumin levels, lower creatinine, and were less likely to be on immunosuppressant therapy. The incidence of in-hospital/30-day stroke after TAVR did not differ between CPS and non-CPS patients (0.0% vs. 1.9%; p = 0.198). Unadjusted analyses at one-year showed a lower occurrence of the composite endpoint in CPS patients compared non-CPS patients (8.3% vs. 17.0%; p = 0.034). After adjustment, the hazard ratio (Adj HR) for the CPS group was no longer significantly associated with a lower composite endpoint (Adj HR = 0.609, 95% CI 0.244–1.523; p = 0.289). Both unadjusted (p = 0.233) and adjusted (p = 0.132) analyses showed no difference in the incidence of stroke at one-year. Conclusions: Our study demonstrates that in a “real-world” setting, the Sentinel CPS device is more likely to be used in healthier and less complex patients. In analyses adjusted for illness severity and patient complexity, CPS use did not have a significant effect on the incidence of in-hospital/30-day stroke or the composite endpoint of death, stroke, and bleeding/vascular events at one-year.