Background: Therapeutic hypothermia (TH) is known as the most efficient treatment for reducing brain injury during postresuscitation care. However, there have been limited data that show the benefits of prolonged TH, especially in a clinically relevant large animal cardiac arrest model. The aim of this study as to investigate whether 48 hrs of therapeutic hypothermia (TH) is more effective to attenuate brain apoptosis than 24 hrs and to determine whether the antiapoptotic effects of TH are associated with the suppressions of the cleavage of protein kinase C-delta (δPKC), the cytosolic release of cytochrome c, and the cleavage of caspase 3 in a swine cardiac arrest model. Methods: This was a prospective laboratory study conducted on male domestic pigs. After 6 mins of no flow time that was induced by ventricular fibrillation, cardiopulmonary resuscitation was provided, and the return of spontaneous circulation (ROSC) was achieved. The animals were randomly assigned to the following groups: sham, normothermia (NT), 24 hrs of TH (24-TH), or 48 hrs (48-TH). TH (core temperature, 32~34℃) was maintained for 24 or 48 hrs post-ROSC, and the animals were rewarmed for 8 hrs. At 60 hrs post-ROSC, the animals were sacrificed, and brain tissues were harvested. We examined cellular apoptosis and neuronal damage in the brain hippocampal cornu ammonis 1 region. We also measured the cleavage of δPKC, the cytosolic release of cytochrome c, and the cleavage of caspase 3 in the hippocampus. Results: The 48-TH attenuated cellular apoptosis and neuronal damage when compared to NT. There was also a decrease in the cleavage of δPKC, the cytosolic release of cytochrome c, and the cleavage of caspase 3. However, 24-TH did not significantly attenuate cellular apoptosis or neuronal damage. Conclusion: We found that 48 hrs of TH was more effective in attenuating brain apoptosis than 24 hrs of TH. We also found that the antiapoptotic effects of TH were associated with the suppressions of the cleavage of δ PKC, the cytosolic release of cytochrome c, and the cleavage of caspase 3.