We examined the in vivo immunosuppressive effect of alpha-fetoprotein (AFP) by infection experiments with Listeria monocytogenes, a facultative intracellular pathogen, using transgenic mice that express and produce human AFP. The transgenic mice showed diminished ability to eliminate bacteria in the early stage of infection. In addition, the transgenic mice had significantly reduced production of IFN-gamma in their livers and sera and TNF in their spleens. These data indicate that AFP suppresses the production of the cytokines, IFN-gamma and TNF in NK cells and macrophages so that the mice could not eliminate the bacteria. This is the first report that AFP has an in vivo immunosuppressive effect on cytokine production related to the early host defense against infection by microorganisms.