Background: Pharmacological histone deacetylase (HDAC) inhibitors, such as known anticonvulsant valproic acid (VPA), demonstrate cytoprotective effects and increase acetylation of nuclear histones, promoting transcriptional activation of de-regulated genes. Therefore, we examined protective effects of VPA administration in lethal hemorrhage and analyzed the patterns of hepatic histone acetylation. Methods: Male Wistar Kyoto rats were pretreated with VPA (n = 10) and 2-methyl-2-pentenoic acid (2M2P), structural VPA analog with limited HDAC inhibiting activity (2M2P; n = 8), at 300 mg/kg/dose, administered subcutaneously, 24 hour and immediately before lethal, if untreated, hemorrhage was induced by removing the 60% of total blood volume. Both drugs were dissolved in normal saline (NS) and rats pretreated with corresponding volume of NS served as control group (n = 8). Time to death, the degree of histone acetylation in liver, HDAC activity and markers of cytotoxicity (alpha-glutathione S-transferase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and lactate), and apoptosis were analyzed. Results: VPA-pretreated animals demonstrated five-fold increase in survival duration. At 12 hours posthemorrhage, 70% (VPA) and 12% (2M2P) pretreated rats were alive versus 0% in NS group. Hyperacetylation of histones H2A, H3, and H4 indicated the presence of active genes and correlated with survival (VPA > 2M2P > NS). Hemorrhage-induced increases in lactate, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were alleviated by VPA. Moreover, alpha-glutathione S-transferase release, indicative of liver damage, was completely abolished. Conclusion: VPA offers considerable protection in severe hemorrhagic shock. The role of HDAC inhibition is suggested in mediating prosurvival actions of VPA.