BACKGROUND To explore the effects of the respiratory rate (RR) on the venous-to-arterial CO2 tension difference (gapCO2) in septic shock patients undergoing volume mechanical ventilation. METHODS Adult patients with septic shock underwent volume mechanical ventilation between October 2015 and October 2016. RR was started at 10 breaths/min, and 2 breaths/min were added every 60 min until 16 breaths/min was reached. At every point, central venous and arterial blood gas measurements were obtained simultaneously. RESULTS In this study, gapCO2 induced by hyperventilation significantly increased, while the central venous carbon dioxide pressure (PvCO2) and the partial pressure of CO2 (PaCO2) in arteries decreased. The decreasing trend of the PaCO2 was more obvious than that of the PvCO2. HCO3- and ctCO2 were markedly decreased, when the RR was increased (P < 0.05). Central venous oxygen saturation (ScvO2) had a decreasing trend between 14 (77.1 ± 8.3%) and 16 (75.2 ± 8.7%) breaths/min; however, the difference was not significant. CONCLUSIONS In septic patients undergoing ventilation, respiratory alkalosis induced by hyperventilation caused an increase in the gapCO2. Clinicians should cautiously interpret the gapCO2 in hemodynamically stable ventilated septic shock patients and its relationship with low cardiac output and inadequate perfusion.