Cardiopulmonary bypass (CPB) induces inflammation partly via leukocyte activation. We conducted a first-in-human pilot study assessing the feasibility and perioperative safety of a novel activated leukocyte adsorption device during CPB. The leukocyte adsorber was integrated into the CPB circuit of adults undergoing cardiac surgery. Numbers of CD11b⁺ neutrophils were measured by flow cytometry from baseline until 48 h after surgery. The primary endpoint was the rate of CD11b⁺ neutrophil removal between before and immediately after adsorption. Secondary outcomes included inflammatory biomarkers, hemostasis indices, safety events and SOFA score at 24 h after surgery. Six patients completed follow-up. The removal rate varied widely (mean, − 15.8 ± 43.4%; range, − 79.4% to 18.6%; median, 4.0%). IL-6, IL-8, and IL-10 peaked at 6 h and declined by 24–48 h after surgery. Peak temperature was 37.6 ± 0.3 °C and organ dysfunction was mild (SOFA score 3.83 ± 0.75). One patient developed acute kidney injury, but none suffered stroke, respiratory failure, major cardiovascular or cerebrovascular events, or device-related adverse events. Our novel leukocyte adsorption during CPB appears feasible and safe. No conclusions regarding efficacy can be drawn. Further larger controlled studies are required. Trial registration: Chinese Clinical Trial Registry (ChiCTR2500109580).