Mycobacterium abscessus is an emerging rapidly growing mycobacterium that causes tuberculous-like lesions in humans. We studied the immune control of this organism in C57BL/6 mice challenged intravenously with 10(7) CFU. Bacteria were eliminated from both the spleen and the liver within 90 days, and liver histology showed organized granulomatous lesions. A T- and B-cell requirement was investigated by challenging Rag2-/-, Cd3epsilon-/-, and muMT-/- mice. Rag2-/- and Cd3epsilon-/- mice were significantly impaired in the ability to clear M. abscessus from the liver and spleen, and muMT-/- mice were significantly impaired in the ability to clear M. abscessus from the liver, suggesting that infection control was primarily T cell dependent in the spleen and both T and B cell dependent in the liver. The liver granulomatous response was similar to that of wild-type controls in muMT-/- mice but completely absent in Cd3epsilon-/- and Rag2-/- mice. We studied the involvement of gamma interferon (IFN-gamma) and tumor necrosis factor (TNF) by challenging C57BL/6 mice deficient in the IFN-gamma receptor (Ifngr1-/-) and in TNF (Tnf-/-). Ifngr1-/- mice were significantly impaired in M. abscessus control both in the spleen and in the liver, and granulomas were profoundly altered. The effect was even more substantial in Tnf-/- mice; they failed to control M. abscessus infection in the liver and died within 20 to 25 days after infection with many hepatic inflammatory foci and major lesions of ischemic necrosis in the liver and kidney. These features were not observed with the closely related species M. chelonae. T-cell immunity, IFN-gamma, and TNF are central factors for the control of M. abscessus in C57BL/6 mice, as they are for the control of pathogenic slowly growing mycobacteria.