Background: Cardiac surgery is associated with a substantial risk of major adverse events. Although carbon dioxide (CO₂)-derived variables such as venous-to-arterial CO₂ difference (ΔPCO₂), and PCO₂ gap to arterial–venous O₂ content difference ratio (ΔPCO₂/C_(a−cv)O₂) have been successfully used to predict the prognosis of non-cardiac surgery, their prognostic value after cardiopulmonary bypass (CPB) remains controversial. This hospital-based study explored the relationship between ΔPCO₂, ΔPCO₂/C_(a−cv)O₂ and organ dysfunction after CPB.Methods: We prospectively enrolled 114 intensive care unit patients after elective cardiac surgery with CPB. Patients were divided into the organ dysfunction group (OI) and non-organ dysfunction group (n-OI) depending on whether organ dysfunction occurred or not at 48 h after CPB. ΔPCO₂ was defined as the difference between central venous and arterial CO₂ partial pressure.Results: The OI group has 37 (32.5%) patients, 27 of which (23.7%) had one organ dysfunction and 10 (8.8%) had two or more organ dysfunctions. No statistical significance was found (P = 0.84) for ΔPCO₂ in the n-OI group at intensive care unit (ICU) admission (9.0, 7.0–11.0 mmHg), and at 4 (9.0, 7.0–11.0 mmHg), 8 (9.0, 7.0–11.0 mmHg), and 12 h post admission (9.0, 7.0–11.0 mmHg). In the OI group, ΔPCO₂ also showed the same trend [ICU admission (9.0, 8.0–12.8 mmHg) and 4 (10.0, 7.0–11.0 mmHg), 8 (10.0, 8.5–12.5 mmHg), and 12 h post admission (9.0, 7.3–11.0 mmHg), P = 0.37]. No statistical difference was found for ΔPCO₂/C_(a−cv)O₂ in the n-OI group (P = 0.46) and OI group (P = 0.39). No difference was detected in ΔPCO₂, ΔPCO₂/C_(a−cv)O₂ between groups during the first 12 h after admission (P > 0.05). Subgroup analysis of the patients with two or more failing organs compared to the n-OI group showed that the predictive performance of lactate and Base excess (BE) improved, but not of ΔPCO₂ and ΔPCO₂/C_(a−cv)O₂. Regression analysis showed that the BE at 8 h after admission (odds ratio = 1.37, 95%CI: 1.08–1.74, P = 0.009) was a risk factor for organ dysfunction 48 h after CBP.Conclusion : ΔPCO₂ and ΔPCO₂/C_(a−cv)O₂ cannot be used as reliable indicators to predict the occurrence of organ dysfunction at 48 h after CBP due to the pathophysiological process that occurs after CBP.