Cytokines are important mediators of the inflammatory host response against infectious agents. In this study, the role of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the elimination of a primary infection with highly virulent Yersinia enterocolitica serotype 0:8 strain WA-P has been investigated in C57BL/6 mice. The injection of anti-TNF-alpha or anti-IFN-gamma antibodies ("serotherapy") prior to the intravenous challenge of a sublethal dose of Y. enterocolitica caused an increased bacterial net-growth in the spleens, although this effect was more pronounced for anti-TNF-alpha treatment. The later treatment with anti-TNF-alpha or anti-IFN-gamma antibodies on day 3 post infection likewise abrogated resistance to Y. enterocolitica and, subsequently, led to death from progressive infection. Our data demonstrate for the first time that the endogenous production of both the cytokines TNF-alpha and IFN-gamma is required for the restriction of a primary Y. enterocolitica infection in mice.