Sepsis represents the systemic inflammatory response caused by microbial infection in blood. Given the complexity of its pathophysiology, current extracorporeal blood purifications are based on non-selective removal of inflammatory mediators which have had limited success and feasibility in clinical settings. In this work, we developed a microfluidic blood purification approach for non-specific removal of bacteria and inflammatory cellular components (platelets and leukocytes) from whole blood using cell margination. We performed continuous blood filtration in vivo in mice and demonstrated long term modulation of host inflammatory response in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP).