We have previously shown that IL-6 is a major cytokine in the serum of mice infected with the intracellular bacterium Listeria monocytogenes, and that injection of rIL-6 before, but not after, infection promotes the recovery of mice from listeriosis. Here we demonstrate that IL-6 is required in the early stages of infection, in that injection of anti-IL-6 Ab 24 or 4 h before infection, but not 24 h after, led to a massive increase in bacterial numbers 4 or more days after infection. On the other hand, injection of rIL-6 before infection significantly suppressed bacterial numbers in the liver and spleen 3 to 4 days after infection and increased the production of IFN-gamma by in vitro cultured CD4+ and CD8+ T cells in response to specific Ag. rIL-6 did not protect SCID mice, which lack both T and B lymphocytes, against Listeria infection. The protective effect of rIL-6 was neutralized by the injection of Ab to IFN-gamma. We conclude that IL-6 plays an essential role in the activation of T cells to produce IFN-gamma, the cytokine that is central to acquired cellular resistance to intracellular bacteria.