Alteration of tissue perfusion is a main contributor to organ dysfunction in high-risk surgical patients. The difference between venous carbon dioxide and arterial carbon dioxide pressure (pCO2 gap) has been described as a parameter reflecting tissue hypoperfusion in critically ill patients who are insufficiently resuscitated. The pCO2 gap/CavO2 ratio has also been described as an indicator of the respiratory quotient, thus the relationship between DO2 and VO2. Most of the knowledge about the pCO2 gap and the pCO2 gap/CavO2 ratio has come from studies in the literature on animal models or intensive care unit (ICU) patients. To date, publications pertaining to the operative setting are sparse. In the present review, we will first discuss the physiological background of the pCO2 gap and CO2-O2 derived parameters used in the operating room. Few studies have focused on the clinical relevance of the pCO2 gap in high-risk non-cardiac surgical patients. Prospective observational studies with a small sample size and retrospective studies have shown that the pCO2 gap may be a useful complementary tool to identify patients who remain insufficiently optimized hemodynamically. In a few studies, a high pCO2 gap was associated with postoperative complications following non-cardiac high-risk surgery. Results of observational studies conducted in patients undergoing cardiac surgery are contradictory. We focused on the divergence between non-cardiac surgery, cardiac surgery, and septic critically ill patients. When analyzing the literature, we can find some explanations for the discrepancies in the published results between cardiac and non-cardiac surgery. Finally, we will discuss the clinical utility of the pCO2 gap in high-risk surgical patients.