Background: High volume hemodiafiltration (HVHDF) has been used in patients with sepsis to potentially improve hemodynamics and increase survival rates. We aimed to assess the effect of HVHDF on oxygenation in mechanically ventilated septic patients. We hypothesized that HVHDF could improve oxygenation. Methods: In this prospective, non-blinded, single-institution randomized trial, forty patients were randomly assigned to receive HVHDF (n = 20) or not (n = 20). Patients in the HVHDF group received HVHDF at a prescribed dose of 70 ml/kg/ hours for 48 hours in addition to their usual treatments.  Results: At 24 hours and 48 hours after the initiation of HVHDF, the arterial oxygen pressure (PaO₂), the ratio of arterial oxygen pressure to the fraction of inspired oxygen (PaO₂/ FiO₂ ratio), and jugular venous oxygen saturation (S_JVO₂) were all significantly higher in the HVHDF group compared to the non-HVHDF group (P < 0.05). Compared to the non-HVHDF group, the alveolar-arterial oxygen pressure difference (P_A-aO₂) and serum Interleukin- 6 were significantly lower, dynamic compliance increased more significantly, and plateau pressure decreased more significantly in the HVHDF group (P < 0.05) at 48 hours after initiation of HVHDF.  
Duration for weaning from mechanical ventilation (MV) was significantly shorter in the HVHDF group (P = 0.001). However, serum lactate levels, success of weaning from MV, and 28-day survival were not different between the groups (P > 0.05). Conclusions: In mechanically ventilated septic patients, treatment with HVHDF, in addition to standard therapies, improved oxygenation and ventilatory function, and reduced the duration of MV.