Normal human macrophages respond to infection with Mycobacterium avium, serovar 4, by producing tumor necrosis factor (TNF)-α, which mediates apoptosis, and by elaborating interleukin (IL)-10, a TNF-α antagonist. We show that IL-10 down-regulates apoptosis by inhibiting the TNF-α production of the inoculated macrophages and by inducing the release of soluble TNF receptor type 2 from the macrophages, which leads to inactivation of TNF-α. These experiments suggest that induction of IL-10 production is a virulence factor that creates an intracellular sanctuary for the bacteria that is inaccessible to the defense mechanisms of the host.