We tested the hypothesis that obesity influences the pharmacodynamics of volatile general anesthetics (VGAs) by comparing effects of anesthetic exposure on mortality from traumatic brain injury (TBI) in lean and obese Drosophila melanogaster. We induced TBI with a High-Impact Trauma device. Starvation-selection over multiple generations resulted in an obese phenotype (SS flies). Fed flies served as lean controls (FC flies). Adult (1-7 day old) SS and FC flies were exposed to equianesthetic doses of isoflurane or sevoflurane either before or after TBI. The principal outcome was percent mortality 24 hours after injury, expressed as the Mortality Index at 24 hours (MI24). TBI resulted in lower MI24 in FC than in SS flies (21 (2.35) and 57.8 (2.14), respectively n= 12, p=0.0001). Preexposure to isoflurane or sevoflurane preconditioned FC flies to TBI reducing the risk of death to 0.53 [0.25 to 1.13] and 0.82 [0.43 to 1.58], respectively, but had no preconditioning effect in SS flies. Postexposure to isoflurane or sevoflurane increased the risk of death in SS flies. Only postexposure to isoflurane increased the risk in FC flies (1.39 [0.81 to 2.38]). Thus, obesity affects the pharmacodynamics of VGAs, thwarting the preconditioning effect of isoflurane and sevoflurane in TBI.