Significance Expression of the adenovirus protein E4orf4 alone in cultured mammalian cells prompts noncanonical apoptosis that is more efficient in oncogene-transformed cells than in normal cells. Here, E4orf4 activity in a whole organism ( Drosophila melanogaster ) is described, leading to three significant conclusions: ( i ) E4orf4-induced cell death is an evolutionarily conserved process; ( ii ) E4orf4 induces a distinctive mode of cell death, differing from well-characterized cell death mechanisms; and ( iii ) E4orf4 activates cell death but concomitantly inhibits it, thus minimizing damage to normal tissues. The last finding suggests a possible explanation for the differential effect of E4orf4 in normal and cancer cells.