c-Fos is a component of transcription factor AP-1. We show that macrophages lacking c-Fos exhibit enhanced production of proinflammatory cytokines, potentiated NF-kappaB phosphorylation, and increased cell death following Salmonella enterica serovar Typhimurium infection. Furthermore, mice lacking c-Fos are highly susceptible to infection, suggesting that c-Fos confers resistance to Salmonella infection in mice.