- Introduction Acetaminophen (APAP) intoxication is a major cause of acute liver failure. Alginate, an anionic polysaccharide, was previously shown as a macroporous scaffold, to reduce liver inflammation and sustain hepatic synthetic function, when implanted on liver remnant after extended partial hepatectomy. In the recent study we wanted to examine in a model of APAP intoxication the potential of a specially formulated alginate solution to prevent APAP toxicity. Methods Three alginate solutions from low (30–50 kDa, VLVG), medium (100 kDa, LVG54) and high (150 kDa, LVG150) molecular weights were examined. Mice were orally administered with the alginate solution before, with and after APAP administration and were compared to control mice which received vehicle only. All mice were euthanized 24 h after APAP administration. Liver enzyme, blood APAP, IL-6 and liver histology including Ki-67 proliferation, IgG necrosis and nitrotyrosine staining were studied. Results VLVG- treated mice presented low ALT levels while 20–40 fold increase was demonstrated in control mice. The effect of LVG solutions was marginal. Accordingly, liver histology was normal with no hepatocytes proliferation in the VLVG group while massive centrilobular necrosis, increased nitrotyrosine staining and high proliferation appeared in livers of control mice. APAP blood levels were comparable in the two groups. Treatment with VLVG was associated with prevention of increase of IL-6 serum levels. Conclusion VLVG, a novel alginate solution, alleviated the liver toxicity and inhibited oncotic necrosis and related immune-mediated damage. VLVG may serve as a novel hepato-protector and prevent drug induced liver injury.