In humans, fulminant hepatic failure (FHF) is frequently associated with increased factor VIII (FVIII) levels, despite widespread liver cell death. The mechanisms leading to increased FVIII levels and cellular sites of this enhanced FVIII production are poorly understood. We studied the effect of total hepatectomy in pigs, a large-animal model of FHF, on the expression of plasma and tissue FVIII during 24-hour follow-up. Tissue FVIII expression was determined before and 24 h after hepatectomy, both at the mRNA level and immunohistochemically. The expression of plasma and tissue von Willebrand factor (VWF), the natural stabilizing carrier protein of FVIII, was also measured. Total hepatectomy elicited a gradual and sustained twofold elevation of circulating FVIII, whereas FVIII mRNA levels in various organs did not increase after hepatectomy. The half-life of FVIII increased from 7.7 to 10.3 h and VWF levels were also elevated in anhepatic pigs. The increase in the half-life of FVIII and increased levels of VWF were not sufficient to explain the rise in plasma FVIII levels. At the protein level, prominent changes in the cellular distribution of FVIII were seen in spleen and kidney. These observations suggest that in this model of FHF the lack of hepatic FVIII synthesis is adequately compensated by other organs, notably spleen and kidneys.