alpha 1-Acid glycoprotein (AGP) is an acute phase protein produced by hepatocytes. Although its exact biological function remains controversial, it was shown to protect galactosamine-sensitized or normal mice against hepatitis and lethal shock induced by tumor necrosis factor (TNF). Rat-AGP-transgenic mice, constitutively producing several mg AGP per ml serum were tested for their response to a combined challenge with TNF and D-(+)-galactosamine. A previously characterized, single transgenic line (9.5-5) was used. In contrast to our expectations both heterozygous or homozygous transgenic mice were not protected by the endogenously overproduced AGP. However, both transgenic and non-transgenic mice were protected by pretreatment with interleukin-1, an effect which we believe is mediated by the induction of acute phase proteins like AGP. Furthermore, both types of mice were protected by exogenous bovine AGP, suggesting that the lack of protection by endogenous AGP is not because of a repressed response to AGP. Finally, we demonstrate that purified AGP from the serum of transgenic mice is as protective as the AGP from non-transgenic mice or rats. The results suggest that AGP is protective only when its concentration is rapidly induced, perhaps because the endogenous steady state synthesis of AGP, in non-transgenic as well as transgenic mice, is coupled to the production of an AGP-binding factor. This study provides an interesting example of differences in outcome to a lethal challenge between an acute administered and a chronically produced protective protein.