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Tumor necrosis factor (TNFα), a cardinal early mediator of the innate host inflammatory response, has been an attractive target for therapeutic intervention in human sepsis. However, pooled data from 12 completed randomized controlled trials show only a very modest impact on mortality in a highly heterogeneous population of patients. To gain insight into the preclinical in vivo biology of TNFα that might aid in better identifying appropriate patient populations for therapeutic intervention, we undertook a systematic review of published reports of preclinical studies assessing the consequences of neutralization of TNFα in models of acute infection or inflammation. We identified 143 reports incorporating 484 unique experimental comparisons in seven different animal species. The effects of neutralization of TNFα in these were quite variable. Neutralization of TNFα was beneficial in endotoxemia, or after systemic challenge with gram-negative organisms, Staphylococcus aureus, or Group B streptococci. On the other hand, neutralization was detrimental in infections caused by Streptococcus pneumoniae, Candida spp., or intracellular pathogens such as Listeria and Mycobacterium tuberculosis, and in models of pneumonia. Treatment was more efficacious when delivered before infectious challenge, and the therapeutic signal increased as the baseline mortality in the placebo group increased. Evidence of neutralization of TNFα bioactivity, and of attenuation of inflammation, was typically accompanied by evidence of impairment of antimicrobial defenses. Multiple specific and nonspecific therapeutic strategies were identified. We conclude that the beneficial effects of TNF in systemic inflammation occur at the cost of impaired antimicrobial defenses, and that a better understanding of the consequences of neutralization of TNFα in vivo could aid in better defining optimal patient populations for therapeutic intervention.