Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme activated by DNA strand breaks, which transfers 50–200 branched chains of ADP-ribose to various nuclear proteins, including itself. PARP is involved in DNA repair under moderate DNA damage but can cause cell death when overactivated, leading to depletion of its substrate, β-nicotinamide adenine dinucleotide (NAD+), and ATP. This study shows that PARP-deficient (PARP-/-) mice are protected from necrotic cell death and ATP depletion but not from apoptotic death. PARP activation is an active trigger of necrosis, while other mechanisms mediate apoptosis. PARP overactivation leads to ATP depletion, which may cause necrotic cell death. In experiments, PARP-/- fibroblasts were protected from necrotic death but not from apoptotic death. Necrosis was associated with ATP depletion, while apoptosis was not. PARP-/- mice were not protected against cell death caused by tumor necrosis factor-α and α-CD95 in hepatocytes or γ-irradiation. Cells can die by energy-dependent apoptosis or by necrosis. PARP overactivation depletes ATP, suggesting that necrotic cell death may be selectively associated with PARP overactivation. The study compared cellular models of necrosis and apoptosis using fibroblasts, where DNA-damaging agents like MNNG and hydrogen peroxide caused necrosis at high concentrations, while Fas activation led to apoptosis. PARP-/- fibroblasts were protected from necrotic death but not from apoptotic death. Necrosis was associated with ATP depletion, while apoptosis was not. PARP-/- fibroblasts showed no PARP cleavage or internucleosomal DNA fragmentation, indicating that caspases were not activated in MNNG-induced necrotic cell death. Fas activation, on the other hand, induced apoptosis without ATP depletion, and PARP cleavage was observed in Fas-activated fibroblasts but not in MNNG-treated cells. These findings suggest that PARP activation regulates the mode of cell death by influencing intracellular ATP levels. PARP deletion protects against necrotic but not apoptotic cell death, explaining discrepancies in previous studies on PARP's role in cell death. PARP inhibitors block necrotic cell death but not apoptosis, indicating a consistent link between PARP and necrosis. PARP's abundance and high catalytic activity enable its overactivation to mediate the switching of cell death modes. PARP activation is an active process in necrotic cell death, and drugs that inhibit PARP may be therapeutic in conditions where necrosis is the predominant mode of cell death.Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme activated by DNA strand breaks, which transfers 50–200 branched chains of ADP-ribose to various nuclear proteins, including itself. PARP is involved in DNA repair under moderate DNA damage but can cause cell death when overactivated, leading to depletion of its substrate, β-nicotinamide adenine dinucleotide (NAD+), and ATP. This study shows that PARP-deficient (PARP-/-) mice are protected from necrotic cell death and ATP depletion but not from apoptotic death. PARP activation is an active trigger of necrosis, while other mechanisms mediate apoptosis. PARP overactivation leads to ATP depletion, which may cause necrotic cell death. In experiments, PARP-/- fibroblasts were protected from necrotic death but not from apoptotic death. Necrosis was associated with ATP depletion, while apoptosis was not. PARP-/- mice were not protected against cell death caused by tumor necrosis factor-α and α-CD95 in hepatocytes or γ-irradiation. Cells can die by energy-dependent apoptosis or by necrosis. PARP overactivation depletes ATP, suggesting that necrotic cell death may be selectively associated with PARP overactivation. The study compared cellular models of necrosis and apoptosis using fibroblasts, where DNA-damaging agents like MNNG and hydrogen peroxide caused necrosis at high concentrations, while Fas activation led to apoptosis. PARP-/- fibroblasts were protected from necrotic death but not from apoptotic death. Necrosis was associated with ATP depletion, while apoptosis was not. PARP-/- fibroblasts showed no PARP cleavage or internucleosomal DNA fragmentation, indicating that caspases were not activated in MNNG-induced necrotic cell death. Fas activation, on the other hand, induced apoptosis without ATP depletion, and PARP cleavage was observed in Fas-activated fibroblasts but not in MNNG-treated cells. These findings suggest that PARP activation regulates the mode of cell death by influencing intracellular ATP levels. PARP deletion protects against necrotic but not apoptotic cell death, explaining discrepancies in previous studies on PARP's role in cell death. PARP inhibitors block necrotic cell death but not apoptosis, indicating a consistent link between PARP and necrosis. PARP's abundance and high catalytic activity enable its overactivation to mediate the switching of cell death modes. PARP activation is an active process in necrotic cell death, and drugs that inhibit PARP may be therapeutic in conditions where necrosis is the predominant mode of cell death.