Introduction: Irreversible Electroporation (IRE) is highly dependent on the electrical conductivity of the tissue and the high conductivity of tumor tissue, which leads to a lower field than in the surrounding healthy tissue. Hypersaline Infusion (HI) through the portal vein focuses IRE on scattered liver tumors, by creating a differential conductivity between the different types of tissue. The aim of this study is to determine the effects of the HI protocol on the hepatic and histological biochemical results. Methods: Ten male Sprague Dawley rats were used for HI protocol. Blood samples were collected at pre-, immediately post-, 24-hrs, 72-hrs, 1-week and 3-weeks post-HI. All the animals were sacrificed after one-month follow-up in order to collect histological samples. Results: The mortality rate in this procedure reached 30% (3/10). Only the pH and transaminases at 24-hrs were significantly and directly linked to mortality (p=0.036 and p=0.004, respectively). The three non-surviving animals had a four-time higher AST level at 24-hrs. Natremia normalized at 24-hrs post-HI. Statistically significant differences were found in hepatic necrosis between the non-surviving (n=3) and surviving rats (n=7) (30.67 ± 10.97 vs. 2.86 ± 7.56% respectively, p=0.01). Discussion: HI through the portal system involves a significant risk of possibly lethal cytolysis and acidosis. Therefore, compensatory measures and a reduced saline overload are warranted to improve the survival rates.