A reproducible experimental animal model of fulminant hepatic failure (FHF) resembling the clinical condition is needed. We have developed such a model in the rat by combining resection of the two anterior liver lobes (68% liver mass) with ligation of the right lobes pedicle (24% liver mass), resulting in liver necrosis; the remaining two omental lobes (8% liver mass) are left intact. Adult Sprague-Dawley rats (250-300 g) were used. Survival time was determined in 60 rats. Because maintenance of body temperature at 37 degrees C shortened survival time by half, FHF rats were not warmed during the postinduction period and were allowed to gradually enter a state of mild to moderate hypothermia (29-32 degrees C). Additionally, 42 FHF rats were killed in batches of six rats each 2, 6, 12, 18, 24, 30, and 36 hours postoperatively to evaluate changes in blood chemistry (glucose, lactate, liver function tests, prothrombin time) and to assess liver regenerative response in the residual omental liver lobes (weight, protein content, incorporation of bromodeoxyuridine [BrdU], expression of proliferation cell nuclear antigen [PCNA], mitotic activity), plasma levels of hepatocyte growth factor (HGF) and transforming growth factor beta (TGF-beta1), and tissue expression of the HGF and it's receptor c-met. Rats undergoing partial hepatectomy of 68% (PH; n = 42) and a sham operation (SO; n = 42) served as controls. All SO and PH controls survived. PH rats showed only transient decreases in body temperature, signs of modest early hepatic dysfunction (hyperlactemia, hyperammonemia, prolonged PT time), and normal restitution of liver mass. All FHF rats became comatose by 24 hours postoperatively. Most animals (90%) died within 24-48 hours postoperatively (mean, 39 ± 11 hours). Changes in blood chemistry reflected rapid development of liver failure. Plasma HGF levels were markedly elevated and at all time points were higher than in PH controls (P < .05). At the same time, expression of HGF and c-met messenger RNA in the remnant liver was delayed. Plasma TGF-beta1 levels increased early (18 hours) and remained twofold to threefold higher than that of PH and SO controls (P < .05). There was only a 20% increase in the weight of the remnant liver lobes due to swelling. No hepatocytes stained positively for BrdU and PCNA, and none showed mitotic figures. In contrast, all PH controls showed vigorous liver regeneration. In conclusion, we have developed and characterized a novel model of FHF in rats that has a number of physiological and biochemical features seen clinically in FHF, including severely impaired ability of the residual liver tissue to regenerate.