Infective endocarditis is caused by a bacterial infection of the endocardial surface, and despite improvements in surgical interventions and antimicrobial therapy, mortality remains high. Recently published data suggest that intraoperative hemoadsorption therapy might represent a promising treatment option; however, randomized data still lack, and a comparative study on the intraoperative versus intraoperative plus postoperative use of CytoSorb has not yet been performed. We hypothesized that patients developing intraoperative renal failure benefit from additional postoperative CytoSorb treatment in terms of outcome. We examined the application of hemoadsorption therapy in 20 endocarditis patients separated into two groups: (1) sole intraoperative versus (2) intraoperative plus postoperative treatment, with regard to inflammatory and hemodynamic status, the postoperative course including development of complications, extent of extracorporeal organ support, and outcome. Despite an obviously more pronounced disease severity in the intraoperative plus postoperatively treated patients as evidenced by a higher initial European System for Cardiac Operative Risk Evaluation score, higher reoperation rate, longer cardiopulmonary bypass times, a worse inflammatory status, and perioperative development of acute renal failure, we observed a clear and comparable stabilization in hemodynamics and inflammatory parameters in both groups. More importantly and despite a higher rate of postoperative complications and a longer intensive care unit stay, patients from the intraoperative plus postoperative group showed an equal intensive care unit and 90-day survival compared to patients treated only intraoperatively. Our data suggest that postoperative continuation of hemoadsorption treatment might be beneficial in patients with endocarditis who develop perioperative renal failure in combination with severe hemodynamic instability and high-grade intraoperative findings.