Central nervous system (CNS) infections caused by nontuberculous mycobacteria have been described previously, especially in patients with AIDS. To investigate specific aspects of the pathogenesis of this entity, C57BL bg(+)/bg(-) mice were infected intravenously with Mycobacterium avium, and cultures of blood and brain as well as histopathology examination of brain tissue were carried out at several time points up to 6 months after infection. Low-grade inflammatory changes with small aggregates of lymphocytes and macrophages as well as perivascular cuffing were seen early in the infection. A small number of bacteria could be observed in the parenchyma of the choroid plexus. Six months after infection, numerous bacteria were present within the foamy macrophage of the granulomatous lesions along the ventricle and meninges. None of the mice developed clinical signs of meningitis or encephalitis or even died spontaneously during the period of observation. Use of CD18(-/-) knockout mice indicated that transport of the bacterium within neutrophils or monocytes into the brain is unlikely. Mild chronic CNS infection developed in the mice during sustained systemic M. avium infection, similar to what has been reported in most human cases.