ABSTRACT: When hemoglobin (Hb) is fully saturated with oxygen, the additional gain in oxygen delivery (DO2) achieved by increasing the fraction of inspired oxygen (FiO2) is often considered clinically insignificant. In this study, we evaluated the change in DO2, interrogated by mixed venous oxygen saturation (SvO2), in response to a change in FiO2 of 0.5 during cardiac surgery. When patients were hemodynamically stable, FiO2 was alternated between 0.5 and 1.0 in on-pump cardiac surgery patients (pilot study), and between 0.3 and 0.8 in off-pump coronary artery bypass grafting patients (substudy of the CARROT trial). After the patient had stabilized, a blood gas analysis was performed to measure SvO2. The observed change in SvO2 (ΔSvO2) was compared to the expected ΔSvO2 calculated using Fick's equation. A total 106 changes in FiO2 (two changes per patient; total 53 patients; on-pump, n = 36; off-pump, n = 17) were finally analyzed. While Hb saturation remained near 100% (on-pump, 100%; off-pump, mean [SD] = 98.1% [1.5] when FiO2 was 0.3 and 99.9% [0.2] when FiO2 was 0.8), SvO2 changed significantly as FiO2 was changed (the first and second changes in on-pump, 7.7%p [3.8] and 7.6%p [3.5], respectively; off-pump, 7.9%p [4.9] and 6.2%p [3.9]; all P < 0.001). As a total, regardless of the surgery type, the observed ΔSvO2 after the FiO2 change of 0.5 was ≥ 5%p in 82 (77.4%) changes and ≥ 10%p in 31 (29.2%) changes (mean [SD], 7.5%p [3.9]). Hb concentration was not correlated with the observed ΔSvO2 (the first changes, r = - 0.06, P = 0.677; the second changes, r = - 0.21, P = 0.138). The mean (SD) residual ΔSvO2 (observed - expected ΔSvO2) was 0%p (4). Residual ΔSvO2 was more than 5%p in 14 (13.2%) changes and exceeded 10%p in 2 (1.9%) changes. Residual ΔSvO2 was greater in patients with chronic kidney disease than in those without (median [IQR], 5%p [0 to 7] vs. 0%p [- 3 to 2]; P = 0.049). DO2, interrogated by SvO2, may increase to a clinically significant degree as FiO2 is increased during cardiac surgery, and the increase of SvO2 is not related to Hb concentration. SvO2 increases more than expected in patients with chronic kidney disease. Increasing FiO2 can be used to increase DO2 during cardiac surgery.