BACKGROUND: Exposure to anesthetics is common in the majority of early survivors of life-threatening injuries. Whether and to what degree general anesthetics influence outcomes from major trauma is unknown. Potential confounding effects of general anesthetics on outcome measures are usually disregarded. We hypothesized that exposure to isoflurane or sevoflurane modulates the outcome from blunt trauma with traumatic brain injury (bTBI). METHODS: We tested the hypothesis in a novel model of bTBI implemented in Drosophila melanogaster. Fruit flies of the standard laboratory strain w were cultured under standard conditions. We titrated the severity of bTBI to a mortality index at 24 hours (MI24) of approximately 20% under control conditions. We administered standard doses of isoflurane and sevoflurane before, before and during, or after bTBI and measured the resulting MI24. We report the MI24 as mean ± standard deviation. RESULTS: Isoflurane or sevoflurane administered for 2 hours before bTBI reduced the MI24 from 22.3 ± 2.6 to 10.4 ± 1.8 (P < 10, n = 12) and from 19.3 ± 0.9 to 8.9 ± 1.1 (P < .0001, n = 8), respectively. In contrast, administration of isoflurane after bTBI increased the MI24 from 18.5% ± 4.3% to 25.3% ± 9.1% (P = .0026, n = 22), while sevoflurane had no effect (22.4 ± 7.1 and 21.5 ± 5.8, n = 22). CONCLUSIONS: In a whole animal model of bTBI, general anesthetics were not indifferent with respect to early mortality. Therefore, collateral effects of general anesthetics should be considered in the interpretation of results obtained in vertebrate trauma models. Invertebrate model organisms can serve as a productive platform to interrogate anesthetic targets that mediate collateral effects and to inform trauma research in higher organisms about the potential impact of anesthetics on outcomes.