Murine infection with the facultative intracellular pathogen Listeria monocytogenes was studied as a model of cell-mediated immunity. Overwhelming lethal infection with Listeria developed when mice were given a secondary challenge with a protein antigen at the same time as Listeria infection. Three days after infection, mice immunized with ovalbumin and then challenged with Listeria and ovalbumin had up to 2.1(10)6 times as many viable Listeria organisms in their spleens as mice challenged only with Listeria. The suppressive effect of secondary challenge with a protein antigen was found to be antigen-specific, transient, and not dependent on route of challenge with either Listeria or ovalbumin. Secondary challenge with a protein antigen suppressed both the primary and the secondary responses to Listeria. Immune serum, or affinity-purified antibody, was found to transfer the suppressive effect to nonimmune mice. These findings demonstrate that acute formation of immune complexes causes a transient state of high susceptibility to infection with an intracellular pathogen. Possible mechanisms for, and implications of, these findings are discussed.