Abstract Body (Do not enter title and authors here): Introduction: Hypothermic circulatory arrest (HCA) is associated with neurological damage. During HCA, antegrade cerebral perfusion (ACP) supports neuroprotection by perfusing the brain with oxygenated blood. Optimal ACP flow rates aim to maintain near-physiological conditions and provide neuroprotection by preventing ischemia and subsequent immune activation, therefore improving cognition and memory. Hypothesis: We hypothesized that an ideal neuroprotective ACP flow rate exists that impacts immune activation and function, resulting in altered levels of peripheral inflammatory proteins, immune reactivity, and cognition. Methods: Animals and Surgery: Eighteen canines were randomized into three groups with different ACP flow rates 2.5, 5, and 10 mL/kg/min. Canines were anesthetized, cannulated for peripheral cardiopulmonary bypass, and cooled to 18 °C. Cognition was assessed using Novel Object Recognition. Peripheral Blood Mononuclear Cell Isolation, Culture, and Challenge: At 48 hours post-operation, blood was collected and serum separated. PBMCs were isolated and cultured; some cells were challenged with lipopolysaccharide (LPS). After 4 and 24hrs of culture, the cells and media were collected. Inflammatory markers were evaluated with ELISA. Results: 24h following HCA, no experimental group demonstrated preference for novelty. 48 hours post-op, canines in the 10 mL/kg/min ACP group had intact and improved cognition and the lowest levels of immune activation and inflammatory biomarkers. Canines receiving 10mL/Kg/min demonstrated preference for the novel objects and nearly doubled interaction time (p<0.05). This improvement in cognition was concomitant with the lowest levels of IL-6, IL-8, TNFa, and MCP-1/CCL2 in the PBMC secretome. Indeed, for PBMC reactivity, flow rate and inflammatory drive were inversely related, with the 2.5 mL/kg/min group secreting the highest levels of IL-6, IL-8, TNFa, and MCP-1/CCL2 at baseline. After the challenge with a secondary inflammatory stimulus in culture (LPS), PBMCs isolated from the 5mL/kg/min group expressed the highest levels of each inflammatory marker, with the lowest response in the 10 mL/kg/min group. Conclusion: Our findings support the incorporation of ACP during cardiac surgery as a reliable neuroprotection strategy in patients undergoing HCA. 10 mL/kg/min ACP flow rate showed evidence of neuroprotection with improved object recognition alongside decreased inflammatory response and reactivity.