OBJECTIVE Hypertonic saline (HTS) solution resuscitation has been used in a variety of clinical settings. The aim of this study was to assess the effect of HTS resuscitation on hemodynamics, systemic oxygenation, and organ damage in a porcine model of severe acute pancreatitis. METHODS Eighteen anesthetized and mechanically ventilated pigs were divided into 3 groups: HTS group, lactated Ringer solution (LR) group, and sham-operated group. Severe acute pancreatitis was induced in the first 2 groups by injecting 5% sodium taurocholate into the pancreatic duct, and the investigation period was 12 hours. Hemodynamic parameters, urine output, oxygenation parameters, and serum parameters were recorded consecutively. Finally, histologic examinations of the kidney, intestine, pancreas, and lung were performed. RESULTS In the HTS group, cardiac output decreased less significantly compared with the LR group. Furthermore, aspartate aminotransferase, creatinine, and lactate levels increased significantly in all animals with severe acute pancreatitis, but the increasing tendency was slower in the HTS group. Nevertheless, the histopathologic analysis revealed similar injuries of the kidney, intestine, pancreas, and lung between the HTS and LR groups. CONCLUSIONS Early administration of HTS generally improves hemodynamics and peripheral oxygenation. Despite these normalized parameters, organ damage could not be diminished to a significant degree during observation.