Introduction: Septic shock is a medical emergency. Various clinical biomarkers have been used to either prognosticate or use them for goal-directed management of the same. The venoarterial difference in the partial pressure of carbon dioxide (Pv-aCO₂ gap) has been used as an alternate marker for assessing tissue hypoperfusion and to predicting mortality. Aim: To determine the therapeutic and prognostic value of central venous to arterial carbon dioxide difference during early resuscitation of critically ill nosocomial septic shock patients. Objectives: The primary objective was to predict 28-day mortality using the Pv-aCO₂ gap. The secondary objectives were to compare the accuracy of lactate clearance, sequential organ failure assessment (SOFA) score against Pv-aCO₂ gap as a predictor of 28-day mortality and to determine the association of fluid resuscitation and its effects on the Pv-aCO₂ gap. Materials and methods: A prospective observational cohort study was performed in a tertiary care intensive care unit (ICU). A total of 50 nosocomial septic shock patients were recruited. They are from either ward admissions or those who stayed in ICU beyond 48 hours. A Pv-aCO₂ gap was measured serially over 0, 3, and 6 hours. Lactate clearance at 6 hours was measured. SOFA score on days 1 and 2 of admission, fluid resuscitation in the first 6 hours, and cumulative fluid balance over 24 hours and 7 days were calculated. The patients were divided into survivors and nonsurvivors according to the outcome at 28 days. Pv-aCO₂ gap was assessed in both groups. The receiver operating characteristic (ROC) curve was plotted to analyze the prognostic value of these variables in predicting 28-day mortality. Data analysis was carried out using the Statistical Package for the Social Sciences (SPSS) version 18.5 package. Results: The median values of the Pv-aCO₂ gap had progressively increased in nonsurvivors (7.17, 7.70, and 8.06 mm Hg) over 0, 3, and 6 hours, respectively, whereas it progressively narrowed (6.84, 6.45, and 6.03 mm Hg) in survivors during the first 6 hours of the resuscitation period. Persistently high Pv-aCO₂ gap at the end of 6 hours of resuscitation was observed in nonsurvivors, which were statistically significant (85.3 vs 43.8%, p = 0.004). Survivors and nonsurvivors received a mean crystalloid volume of 1430.8 ± 431.6 mL, irrespective of their Pv-aCO₂ gap of < or >6 mm Hg. The discriminatory capacity at predicting 28-day mortality for SOFA score on days 1 and 2, lactate clearance at 6 hours, and Pv-aCO₂ gap at 0, 3, and 6 hours were compared. ROC curve analysis showed that SOFA scores on days 1 and 2, lactate clearance at 6 hours, and Pv-aCO₂ gap at 3 and 6 hours had predictive value to prognosticate 28-day mortality. The area under the ROC curve (AUROC) for SOFA score on days 1 and 2 was 0.907 [95% confidence interval (CI) was 0.791–0.971, p < 0.001] and 0.943 (95% CI was 0.839–0.989, p < 0.001) respectively. The AUROC for lactate clearance at 6 hours was 0.938 (95% CI was 0.743–0.947, p < 0.001). AUROC for Pv-aCO₂ gap values at 3 and 6 hours were 0.814 (95% CI was 0.679–0.910, p < 0.001) and 0.865 (95% CI was 0.738–0.945, p < 0.001), respectively. Conclusion: Persistent high Pv-aCO₂ gap can be used as a prognostic marker for predicting 28-day mortality in nosocomial septic shock patients. Pv-aCO₂ gap at 6 hours has almost the same discriminatory capacity as SOFA score on days 1 and 2, and lactate clearance at predicting 28-day mortality. More studies are required to ascertain the value of Pv-aCO₂ gap values in estimating the adequacy of fluid resuscitation in nosocomial septic shock patients.