Genetically susceptible, TNFRp55 gene-deficient (TNFRp55−/−) mice succumb to infection with Mycobacterium avium. Before their death, M. avium-infected TNFRp55−/− mice develop granulomatous lesions that, in contrast to granulomas in wild-type syngeneic mice, undergo acute disintegration. To determine the factors involved in these events, we depleted T cell subsets or neutralized the inflammatory cytokines IFN-γ, IL-12, or TNF in TNFRp55−/− mice infected iv with M. avium. Infected TNFRp55−/− mice treated with a control mAb became moribund between days 26 and 34 postinfection, showing widespread inflammatory cell apoptosis within disintegrating granulomas. In contrast, TNFRp55−/− mice depleted of either CD4+ or CD8+ cells after granuloma initiation stayed healthy until at least day 38 postinfection and showed no signs of granuloma destruction. Neutralization of IL-12, but not of IFN-γ or TNF, also protected M. avium-infected TNFRp55−/− mice from granuloma decomposition and from premature death. Treatment with dexamethasone or with a specific inhibitor of inducible NO synthase did not prevent granuloma dissolution or death of TNFRp55−/− mice. In conclusion, granuloma disintegration in TNFRp55−/− mice is a lethal event that is dependent on IL-12 and that is mediated by an excess of T cells.