Purpose <p>To compare the effects of propofol and remimazolam on peri-operative oxygen supply–demand balance.</p> Methods <p>This prospective quasi-randomized controlled trial was carried out in a single tertiary care university hospital between January and October 2022, with patients (<i>n</i> = 50) aged 18–85&#xa0;years undergoing major abdominal surgery. General anesthesia was induced and maintained with propofol or remimazolam. The primary endpoints were peri-operative oxygen consumption (<i>V</i>O₂) and carbon dioxide production (<i>V</i>CO₂). The secondary endpoints were oxygen delivery (DO₂) and the respiratory quotient (RQ). These were measured using indirect calorimetry and arterial pressure waveform analysis for cardiac output monitoring. Time-series changes in these parameters were analyzed to compare the effects of the anesthetics on oxygen supply–demand balance. The associations among the choice of anesthetic agent, patient characteristics, and VCO₂ levels were investigated.</p> Results <p>Anesthesia induction significantly decreased <i>V</i>O₂, <i>V</i>CO₂, DO₂, and RQ. The reduction in <i>V</i>O₂, <i>V</i>CO₂, DO₂, and RQ in the propofol and remimazolam groups was 17.6% [IQR: -0.55–27.8] vs 17.4% [10.3–31.6] (<i>P</i> = 0.47), 26.1% [5.2–40.5] vs 31.2% [16.2–42.6] (<i>P</i> = 0.59), 24.4% [1.0–35.2] vs 20.7% [15.4–32.8] (<i>P</i> = 0.93), and 10.3% [4.4–16.7] vs 10.4% [-4.7–21.6] (<i>P</i> = 0.71), respectively. A weak association between anesthesia choice and <i>V</i>CO₂ concentrations was observed. Patients with higher <i>V</i>CO₂ were younger, with better cardiac function than those with lower <i>V</i>CO₂.</p> Conclusions <p>Anesthesia induction suppressed metabolism. However, the choice of general anesthetic for scheduled major abdominal procedures did not significantly affect the oxygen supply–demand balance.</p> <p><b>Trial registration:</b> University Hospital Medical Information Network Clinical Trials Registry identifier: UMIN000046531.</p>