Objectives To evaluate the effect of the selective cytopheretic device (SCD) on outcome of severe acute kidney injury (AKI) requiring renal replacement therapy, and to observe the occurrence of adverse events from application of the device. Methods In this study, acute kidney injury was defined as ischemic or nephrotoxic acute tubular necrosis by clinic diagnosis, with at least one nonrenal organ failure or presence of sepsis at the same time. All subjects received standard intensive care treatment with continuous veno-venous hemofiltration (CVVH) in addition to the SCD treatment. Patients enrolled in the trial were compared with the historical case-matched controls from PICARD study with respect to age and Sequential Organ Failure Assessment (SOFA) score. The primary endpoint was in-hospital all cause mortality. Other observation index included urine output change and the occurrence of adverse events. After adjusting for confounders, the Cox model was used to analyze whether SCD combined with CVVH treatment was better than routine CVVH. Results A total of 9 patients were enrolled. In-hospital all cause mortality of SCD combined with CVVH treatment group was 22.2%, significantly lower than historical case-matched control group (77.8%) (p=0.027). Multiple regression analysis identified treatment with SCD as the only significant variable affecting mortality among age, SOFA score, and average change in urine output (SCD vs. CVVH historical cohort, p=0.0222). Mean total urine output in the 9 subjects receiving SCD treatment increased from a baseline of approximately 500 ml/d to more than 2,000 ml/d by day 7 of treatment. In this study, only a few mild adverse events occurred, and no serious adverse events were reported. Conclusion SCD can regulate the immune response by deactivating leukocytes, and therefore improve in-hospital mortality of patients with AKI. The safety of SCD is favorable.