Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme activated by DNA strand breaks, which transfers ADP-ribose to various nuclear proteins, including itself. Overactivation of PARP can lead to cell death by depleting its substrate β-nicotinamide adenine dinucleotide (NAD+) and ATP. This study investigates the role of PARP in cell death, specifically apoptosis and necrosis, using mouse fibroblasts. PARP-deficient (PARP−/−) fibroblasts are protected from necrotic cell death and ATP depletion but not from apoptotic death. The findings suggest that PARP activation triggers necrosis, while other mechanisms mediate apoptosis. PARP overactivation induced by DNA-damaging agents like N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) leads to necrosis and ATP depletion, whereas Fas-induced apoptosis does not deplete ATP. These results indicate that PARP activation is an active trigger of necrosis, providing insights into the regulation of cell death modes.Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme activated by DNA strand breaks, which transfers ADP-ribose to various nuclear proteins, including itself. Overactivation of PARP can lead to cell death by depleting its substrate β-nicotinamide adenine dinucleotide (NAD+) and ATP. This study investigates the role of PARP in cell death, specifically apoptosis and necrosis, using mouse fibroblasts. PARP-deficient (PARP−/−) fibroblasts are protected from necrotic cell death and ATP depletion but not from apoptotic death. The findings suggest that PARP activation triggers necrosis, while other mechanisms mediate apoptosis. PARP overactivation induced by DNA-damaging agents like N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) leads to necrosis and ATP depletion, whereas Fas-induced apoptosis does not deplete ATP. These results indicate that PARP activation is an active trigger of necrosis, providing insights into the regulation of cell death modes.