Background and Aims: Tissue hypoperfusion is reflected by metabolic parameters such as lactate, central venous oxygen saturation (ScvO 2 ) and the veno-arterial CO 2 (vaCO 2 ) difference. We studied the relation of these parameters over time and with outcome in patients with severe septic shock. Materials and Methods: In this single-center, prospective observational cohort study, adult patients (≥18 years) with circulatory shock were included. Echocardiography and simultaneous arterial and venous blood gases were done on enrolment (0 h) and at 24, 48 and 72 h. The partial pressure of CO 2 , lactate and ScvO 2 were recorded from the central venous blood samples. The vaCO 2 was calculated as the difference in CO 2 between paired venous and arterial blood gas samples. Results: Of the 104 patients with circulatory shock, 79 patients (44 males) with septic shock aged 49.8 (standard deviation ± 14.6) years and with sequential organ failure assessment (SOFA) score of 11.0 ± 3.4 were included. 71 patients (89.9%) were ventilated (11.4 ± 12.3 ventilator-free days). The duration of hospitalization was 16.6 ± 12.8 days and hospital mortality 50.6%. Lactate significantly decreased over time with a greater decrement in survivors than nonsurvivors (-0.35 vs. -0.10, P < 0.001). For every l/min increase in cardiac output, vaCO 2 decreased by 0.34 mmHg (P = 0.006). There was no association between ScvO 2 and mortality (P = 0.930). 0 h SOFA and vaCO 2 ≤6 mmHg were strongly associated (P = 0.005, P = 0.018, respectively) with higher odds of mortality. However, this association was evident only in those with ScvO 2 >70% and not in ScvO 2 ≤70%. Conclusion: In septic shock, vaCO 2 ≤6 mmHg is independently associated with mortality, particularly in those with normalized ScvO 2 consistent with metabolic microcirculatory abnormalities in these patients.