We have produced interleukin-6 (IL-6)-deficient mice to examine, in vivo, the wide variety of biological activities attributed to this multifunctional cytokine. To investigate the role of IL-6 during infectious disease, IL-6-deficient mice were challenged with sublethal doses of Listeria monocytogenes, a facultative intracellular bacterium. While normal control animals were able to clear the infection, mutant animals exhibited a high mortality rate and showed uncontrolled replication of the bacteria in the spleen and liver at 2 and 3 days postinfection. Sections of infected tissues showed an increase in the number and severity of inflammatory foci. All aspects of this phenotype in the mutant animals were completely reverted upon administration of recombinant murine IL-6 (rIL-6). Various parameters of natural killer (NK) cell and macrophage function were unaffected in the challenge of the mutant animals. However, IL-6-deficient animals failed to mount peripheral blood neutrophilia in response to listeriosis, whereas control animals displayed a prominent neutrophilia in the blood at 24 and 48 h postinfection. Additionally, we analyzed the efficacy of rIL-6 in protecting animals devoid of lymphocytes or devoid of neutrophils during listeriosis. Administration of rIL-6 was protective to animals devoid of lymphocytes, suggesting that the rIL-6 protective effect was not mediated through lymphocytes. In contrast, control and mutant animals depleted of neutrophils were refractory to the rIL-6 protective effect. These data suggest that IL-6 is critical early during listeriosis, perhaps acting by stimulating neutrophils either directly or indirectly. Additionally, these data show a promising therapeutic potential for rIL-6 administration during opportunistic infection.