OBJECTIVE: This study is to evaluate the effect of high-volume hemofiltration (HVHF) and early goal-directed therapy (EGDT) on alveolar-arterial oxygen exchange in patients with refractory septic shock.;-;PATIENTS AND METHODS: Patients were classified into two groups by a prospective cohort study: 86 received both HVHF and EGDT (the HVHF group), and 81 treated with EGDT only (the control group). Alveolar-arterial oxygen pressure was taken at baseline and at days 1, 3, and 7, and respiratory index (RI, ratio of PaO2 alveolar-arterial oxygen pressure difference (PA-aDO2) to arterial oxygen pressure (PaO2) was calculated.;-;RESULTS: At day 7, the levels of central venous and arterial blood oxygen content were significantly higher in the HVHF vs. the control group (both with p < 0.05). The level of oxygen extraction ratio (O2ER) was significantly higher in the HVHF than the control group (p < 0.01). The levels of PA-aDO2 and RI were significantly lower in the HVHF than the control group (p < 0.05 and p < 0.01, respectively). RI and the ratio of PaO2 to the fraction of inspired oxygen were significantly higher in the HVHF than the control group (p < 0.05 and p < 0.01, respectively). The acute physiology and chronic health evaluation score and the sequential organ failure assessment score in the HVHF group were significantly lower compared to the control group (p < 0.01 and p < 0.05, respectively). At day 28, the mortality rate was lower in the HVHF vs. the control group (p < 0.01).;-;CONCLUSIONS: These findings demonstrated that HVHF, when used as an adjunctive therapy to the EGDP protocol, could improve alveolar-arterial oxygen exchange, clinical outcome and survival in patients with refractory septic shock.