TheDrosophila drop-dead(drd) mutant undergoes massive brain degeneration, resulting in sudden death.drdencodes a multi-pass membrane protein possessingnose resistant to fluoxetine (NRF)and putative acyltransferase domains. However, the etiology of brain degeneration that occurs indrdmutant flies is still poorly understood. Herein, we show thatdrdneurodegeneration may be because of an oxygen deficit in the brain. We found that DRD protein is selectively expressed in cells secreting cuticular and eggshell layers. These layers exhibit blue fluorescence upon UV excitation, which is reduced indrdflies. Thedrdtracheal air sacs lacking blue fluorescence collapse, which likely contributes to hypoxia. Consistently, genes induced in hypoxia are up-regulated indrdflies. Feeding of anti-reactive oxygen species agents partially rescue thedrdfrom sudden death. We propose thatdrdflies can provide a non-invasive animal model for hypoxia-induced cell death.