Tumor necrosis factor (TNF) is required in the control of infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. TNF is essential and non-redundant for forming microbiocidal granulomas, and cannot be replaced by other members of the TNF family. We established a model of latent Mtb infection in mice, allowing investigation of the reactivation of latent Mtb as observed in patients receiving TNF-neutralizing therapy used in rheumatoid arthritis and Crohn’s disease. Antibody neutralization of TNF is able to reactivate clinically silent Mtb infection. Using mutant mice expressing solely membrane, but not soluble TNF, we demonstrated that membrane TNF is sufficient to control acute Mtb infection. Therefore, we hypothesize that TNF-neutralizing therapy, sparing membrane TNF, may have an advantage as compared to complete neutralization. In conclusion, endogenous TNF is critical for the control of tuberculosis infection. Genetic absence or pharmacological neutralization of TNF results in uncontrolled infection, while selective neutralization might retain the desired anti-inflammatory effect but reduce the infectious risk.