Background: Lactate as a target for resuscitation in patients with septic shock has important limitations. The PcvCO₂–PaCO₂/CaO₂–CcvO₂ ratio may be used as an alternative for the same. The primary outcome of the study is to evaluate the correlation between serum lactate and PcvCO₂–PaCO₂/CaO₂–CcvO₂ ratio measured at various time points to a maximum of 24 hours in patients with septic shock [mean arterial pressure (MAP) <65 mm Hg]. The secondary outcomes were to study the (1) relationship between the PcvCO₂–PaCO₂/CaO₂–CcvO₂ ratio and lactate clearance at 6, 12, and 24 hours as compared to the initial serum lactate, (2) to ascertain whether the PcvCO₂–PaCO₂/CaO₂–CcvO₂ ratio and the arterial lactate levels in the first 24 hours are able to predict mortality at day 28 of enrollment, and (3) to determine whether the PcvCO₂–PaCO₂/CaO₂–CcvO₂ ratio and arterial lactate are useful in discriminating survivors from nonsurvivors. Materials and methods: Thirty patients with sepsis-induced hypotension who were being actively resuscitated were enrolled. Paired arterial and central venous blood samples were obtained 0.5 hourly till stabilization of MAP and 6 hourly thereafter for the first 24 hours. Patients were followed up to day 28 of enrollment for mortality and organ system failure. Results: A positive correlation was observed between arterial lactate and PcvCO₂–PaCO₂/CaO₂–CcvO₂ ratio at 0, 6, 12, and 18 hours (R = 0.413, p = 0.02; R = 0.567, p = 0.001; R = 0.408, p = 0.025; R = 0.521, p = 0.003, respectively). No correlation was seen between PcvCO₂–PaCO₂/CaO₂–CcvO₂ ratio and lactate clearance. The subgroup analysis showed that PcvCO₂–PaCO₂/CaO₂–CcvO₂ ratio >1.696 at 24 hours of resuscitation predicted 28-day mortality (sensitivity: 80%, specificity 69.2%, area under the receiver operating characteristic curve 0.82). Conclusion: The PcvCO₂–PaCO₂/CaO₂–CcvO₂ ratio and lactate are positively correlated during the first 24 hours of active resuscitation from sepsis-induced hypotension, and a threshold of 1.696 mm Hg/mL/dL at 24 hours significantly differentiates survivors from nonsurvivors (CTRI/2017/11/010342).