Objective To evaluate the effects of fluid resuscitation and large-volume hemofiltration (HVHF) on the Alveolar-arterial oxygen exchange in patients with refractory septic shock. Method A total of 89 intensive care patients with refractory septic shock treated with fluid resuscitation and/or HVHF were enrolled between August 2006 and December 2009. All the patients were randomly divided into two groups. In group A, patients were treated with fluid resuscitation, n = 41 cases) and in group B, patients were treated with large-volume hemofiltration and fluid resuscitation, n =48). The O2 content of central venous blood(CcvO2), arterial oxygen content (CaO2), Alveolar-arterial oxygen pressure difference (P(A-a)DO2), the ratio of arterial oxygen pressure/alveolar oxygen pressure (PaO2/PAO2), respiratory index (RI) and oxygenation index (OI) were checked. The levels of oxygen exchange in two groups were detected by arterial blood gas analysis before treatnent, 24 hour, 72 hour and 7 days after treatment. The APACHE Ⅱ scores in patients with refractory septic shock were measured before and the 7th day after treatment with HVHF and/or fluid resuscitation respectively. Data were analyzed by using t -test and chi-square test to compare the differences and ratio between two groups and were expressed in mean ± standard deviation, and the analysis of variance was done with SPSS version 12.0 software. Results ① The differences in CcvO2 and CaO2 between two groups were[(0.60±0.24) vs. (0.72±-0.28), P ＜0.05 and (0.84±0.43) vs. (0.94±0.46), P ＜0.05]; and the oxygen extraction rates (O2ER) were significantly different between two groups [(28.7±2.4) vs. (21.7±3.4), P<0.01];② The levels of P(A-a)DO2、ratio of PaO2/PAO2、RI and OI in group B were reduced more significantly than in group A (P<0.05 or P<0.01);③The APACHE Ⅱ scores in both groups were gradually reduced after treatment for 7 days, and the APACHE Ⅱscore in group B on the 7th day of treatment were lower than that in group A[(17.2 ± 6.8) vs. (8.2 ± 3.8), P ＜ 0.01]. Conclusions Fluid resuscitation and HVHF could improve alveolar-arterial-oxygen exchange in patients with refractory septic shock, and at the same time decreased the APACHE Ⅱ scores, improving the survival rate of patients.