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Desflurane and propofol are cardioprotective, but relative efficacy is unclear. The aim was to compare myocardial protection of single, simultaneous, and serial administration of desflurane and propofol.Sixty New Zealand White rabbits and 65 isolated Sprague Dawley rat hearts randomly received desflurane, propofol, simultaneous desflurane and propofol, or sequential desflurane then propofol. Rabbits were subdivided to receive either ischemia-reperfusion with temporary occlusion of the left anterior descending artery or a time-matched, nonischemic perfusion protocol, whereas rat hearts were perfused in a Langendorff model with global ischemia-reperfusion. End points were hemodynamic, functional recovery, and mitochondrial uptake of 3H-2-deoxy-D-glucose as an indicator of mitochondrial permeability transition.In rabbits, there were minimal increases in preload-recruitable stroke-work with propofol (P < .001), desflurane (P < .001), and desflurane-and-propofol (P < .001) groups, but no evidence of increases with pentobarbitone (P = .576) and desflurane-then-propofol (P = .374). In terms of end-diastolic pressure–volume relationship, there was no evidence of increase compared to nonischemic controls with desflurane-then-propofol (P = .364), a small but significant increase with desflurane (P < .001), and larger increases with pentobarbitone (P < .001), propofol (P < .001), and desflurane-and-propofol (P < .001).In rat hearts, there was no statistically significant difference in mitochondrial 3H-activity between propofol and desflurane-and-propofol (165 ± 51 × 10−5 vs 154 ± 51 × 10−5 g·mL·min/μmol; P = .998). Desflurane had lower uptake than propofol (65 ± 21 × 10−5 vs 165 ± 51 × 10−5 g·mL·min/μmol; P = .039), but there was no statistically significant difference between desflurane and desflurane-then-propofol (65 ± 21 × 10−5 vs 59 ± 11 × 10−5 g·mL·min/μmol; P = .999).Propofol and desflurane are cardioprotective, but desflurane is more effective than propofol. The added benefit of desflurane is lost when used simultaneously with propofol.