<b><i>Introduction:</i></b> The clinical effectiveness of AN69-oXiris remains unclear. This study aimed to compare the effects of AN69-oXiris and AN69-ST filters on cytokine levels and clinical improvement in septic patients. <b><i>Methods:</i></b> This prospective observational study recruited septic patients who underwent blood purification in the First Affiliated Hospital of Soochow University between December 2019 and May 2020. Patients were assigned to an AN69-oXiris (oXiris) or AN69-ST (ST) group based on their preferred filter. Patients’ clinical data, cytokine levels, and prognostic indicators were analysed at baseline (T0), 24 h after treatment (T1), and at the end of the treatment (T2). <b><i>Results:</i></b> Forty-four patients participated in this study (22 patients in each group). Participants in both groups showed improvements in mean arterial pressure (MAP) values, oxygenation indices, and urinary output, and decreased vasoactive-inotropic scores (VISs), heart rates, lactic acid levels, and serum creatinine levels after blood purification. Reductions in cytokine levels were observed at T1 in both groups. Improvement the haemodynamic status was higher in the oXiris group than in the ST group at T2 (MAP: 79.0 [76.0, 85.0] vs. 77.0 [72.75, 79.25] mm Hg, <i>p</i> = 0.04; VISs: 9.10 [0.00, 16.69] vs. 19.05 [10.60, 26.33], <i>p</i> = 0.03, respectively). Patients in the oXiris group also had lower cytokine levels than those in the ST group at T1 (tumour necrosis factor-α: 24.55 [16.9, 30.15] vs. 30.15 [23.38, 34.13] pg/mL, <i>p</i> = 0.04; interleukin (IL)-6: 66.63 [46.21, 102.20] vs. 125.48 [79.73, 167.97] pg/mL, <i>p</i> = 0.01; IL-8: 53.59 [35.10, 66.01] vs. 63.60 [45.58, 83.37] pg/mL, <i>p</i> = 0.04; IL-10: 13.50 [10.35, 18.68] vs. 17.15 [13.80, 21.95] pg/mL, <i>p</i> = 0.04, respectively). There were no significant differences between the 2 groups regarding hospital mortality, intensive care unit length of stay (LOS), and hospital LOS. <b><i>Conclusion:</i></b> Blood purification using the AN69-oXiris or AN69-ST filter proved useful for septic patients, which was associated with reduced cytokine levels and improved clinical condition. Patients treated with AN69-oXiris had a more remarkable improvement in haemodynamic status and lower cytokine levels than those treated with AN69-ST filter, but there were no differences in clinical outcomes. Further investigations are needed to prove this finding.