Context:The partial pressure of venous to arterial carbon dioxide gradient (PCO2 gap) is considered as an alternative marker of tissue hypoperfusion and has been used to guide treatment for shock.Aims:The aim of this study was to investigate the prognostic value of venous-to-arterial carbon dioxide difference during early resuscitation of patients with septic shock and compared it with that of lactate clearance and Acute Physiology and Chronic Health Evaluation II (APACHE-II) score.Settings and Design:Forty patients admitted to one Intensive Care Unit were enrolled.Subjects and Methods:APACHE-II score was calculated on admission. An arterial blood gas, central venous, and lactate samples were obtained on admission and after 6 h, and lactate clearance was calculated. Patients were classified retrospectively into Group I (survivors) and Group II (nonsurvivors). Pv-aCO2 difference in the two groups was evaluated.Statistical Analysis Used:Data were fed to the computer and analyzed using IBM SPSS software package version 20.0.Results:At T0, Group II showed high PCO2 gap (8.37 ± 1.36 mmHg) than Group I (7.55 ± 0.95 mmHg) with statistically significant difference (P = 0.030). While at T6, Group II showed higher PCO2 gap (9.48 ± 1.47 mmHg) with statistically significant difference (P < 0.001) and higher mean lactate values (62.71 ± 23.66 mg/dl) with statistically significant difference (P < 0.001) than Group I where PCO2 gap and mean lactate values became much lower, 5.91 ± 1.12 mmHg and 33.61 ± 5.80 mg mg/dl, respectively. Group I showed higher lactate clearance (25.42 ± 6.79%) with statistically significant difference (P < 0.001) than Group II (−69.40–15.46%).Conclusions:High PCO2 gap >7.8 mmHg after 6 h from resuscitation of septic shock patients is associated with high mortality.