Mycobacterium avium infects mononuclear phagocytes, which thereby become reservoirs for this pathogen. Currently recommended therapy does not ensure the eradication of intracellular bacteria. Here, we report that M. avium infection in macrophages activates the signal transducer and activator of transcription type 1 (STAT-1) signaling pathway. Fludarabine, an antileukemic drug active against cells that express STAT-1, selectively kills M. avium-infected macrophages. These findings suggest that phosphorylated STAT-1 can enhance the survival of macrophages, promoting their role as persistent reservoirs of M. avium. This work invites research on new combination therapeutic approaches that consist of fludarabine, to kill the macrophage reservoir, and antibacterial agents, to eliminate mycobacteria released from the dead cells.