Serum concentrations of the actin scavenger Gc-globulin are reduced in acute liver failure (ALF). Prospectively, we tested Gc-globulin's value to predict outcome following ALF using sera from 182 patients with ALF from the U.S. ALF Study Group. Admission serum levels of Gc-globulin (normal range: 350-500 mg/L) were studied by an immunonephelometric method. The median (range) serum Gc-globulin level on admission for the entire group was 91 (5-307) mg/L. Gc-globulin levels were significantly higher in spontaneous survivors than in patients who died or underwent transplantation (113 [5-301] mg/L vs. 73 [5-307] mg/L, P < 0.001). Those surviving non-acetaminophen (paracetamol)-induced ALF without transplantation had higher Gc-globulin levels than nonsurvivors (102 [5-301] mg/L vs. 61 [5-232] mg/L, P = 0.002), whereas there was no significant difference in levels between the groups in patients with acetaminophen-induced ALF. A cutoff level of 80 mg/L in the non-acetaminophen group yielded positive and negative predictive values of 85% and 43%, respectively. The corresponding figures for the King's College criteria were 90% and 49%, respectively. In conclusion, we found that Gc-globulin levels were markedly decreased in patients with ALF; the lowest levels were observed in patients who died or were transplanted. In contrast to previous studies, this study demonstrated that Gc-globulin has prognostic value in patients with non-acetaminophen-induced ALF, in the same range as the King's College criteria. Further refinements of the assay would be necessary to make it more accurate and of practical utility.