Cerebral embolic protection (CEP) devices may be a tool to mitigate the perioperative stroke risk in cardiac surgery. However, studies are limited. The aim of this study was to analyze the feasibility, safety, and efficacy of CEP use in high-risk cardiac surgery. Ten high-risk surgical candidates with native valvular heart disease (mainly mitral with severe MAC) or failed bioprosthesis were consecutively enrolled between March 2023 and April 2024. All participants underwent open-heart surgery with use of Sentinel CEP. The CEP device was successfully deployed and recaptured in all cases without any Sentinel-related complications reported. Clearly visible, large deposits of calcium debris were captured. No significant neurological deficits (above mild neurological dysfunction; NIHSS > 5) were reported in any of the patients. Nine patients suffered postprocedural complications ranging from new-onset left bundle branch block to cardiogenic shock. One individual gradually deteriorated and ultimately died. Importantly, her neurological status remained intact throughout the course of the hospitalization. All other patients were discharged in good standing. The current study extends the early experience demonstrating the feasibility and safety of Sentinel CEP in high-risk cardiac surgery. Particularly in the highest-risk patient sub-sets CEP devices may offer advantages reducing the risk of periprocedural episodes and improving outcomes.