Infection of the dental pulp leads to an osteolytic lesion that results from a polymicrobial infection consisting largely of pathogenic anaerobes. Infection causes significant morbidity and mortality mediated by bacterial factors and in some cases by the up-regulation of inflammatory cytokines. The inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF), in particular, play a complex and central role in the responses to microbial pathogens. However, relatively little is known about the significance of these cytokines in protecting the host from focal polymicrobial anaerobic infections. To establish the relative importance of IL-1 and TNF in mediating the response to a mixed anaerobic infection, we inoculated the dental pulp of mice with six anaerobic pathogens containing functional deletions of receptors to IL-1 (IL-1R1−/−), TNF (TNFRp55−/−-p75−/−), or both (TNFRp55−/−-IL-1RI−/−). The results indicate that IL-1 receptor signaling and TNF receptor signaling both play similarly important roles in protecting the host from local tissue damage. However, IL-1 receptor signaling is considerably more important than TNF receptor signaling in preventing the spread of infection into surrounding fascial planes, since IL-1R1−/− but not TNFRp55−/−-p75−/− mice exhibited significantly higher morbidity and mortality. Moreover, all of the fatal infections occurred in male mice, suggesting the importance of gender differences in limiting the impact of these infections.